KR20150088873A - Novel inhibitor compounds of phosphodiesterase type 10a - Google Patents

Abstract

위의 화학식 I에서,
Y¹ 및 Y²는 Het¹에서의 인접한 원자들이고, 이것은 탄소 및 질소로 이루어진 그룹으로부터 독립적으로 선택되며;
k는 0, 1, 2 또는 3이고;
Het¹은 O, S, N 및 N-R^a로부터 선택된 1, 2 또는 3개의 헤테로원자 또는 헤테로원자 모이어티를 환 구성원으로서 갖는 2가 모노사이클릭 5원 또는 6원 헤테로방향족 라디칼, 또는 O, S, N 및 N-R^a로부터 선택된 1, 2, 3 또는 4개의 헤테로원자 또는 헤테로원자 모이어티를 환 구성원으로서 갖는 2가의 융합된 바이사이클릭 8원, 9원 또는 10원 헤테로방향족 라디칼이고;
Het²는 특히 O, S, N 및 N-R^1a로부터 선택된 1, 2 또는 3개의 헤테로원자 또는 헤테로원자 모이어티를 환 구성원으로서 갖는 모노사이클릭 5원 또는 6원 헤트아릴이고;
Cyc는 특히 임의로 치환된 모노사이클릭 5원 또는 6원 헤트아릴 또는 임의로 치환된 융합된 8원, 9원 또는 10원 바이사이클릭 헤트아릴이고;
Ar은 임의로 치환된 페닐렌 또는 임의로 치환된 2가 6원 헤트아릴이고;
R은 Het¹의 탄소 원자에 부착되고, R은 특히 - 할로겐, C₁-C₆-알킬, C₂-C₆-알케닐, C₂-C₆-알키닐, C₁-C₆-알콕시, C₁-C₆-플루오로알킬, C₁-C₆-플루오로알콕시, C₃-C₆-사이클로알킬 등이다.The present invention relates to the use of a compound of formula I as an inhibitor of phosphodiesterase type 10A and its salts and the like, thereby treating or modulating a medical disorder selected from neurological and psychotic disorders and alleviating the symptoms associated with said disorders And to their use for the manufacture of medicaments suitable for reducing the risk of these disorders.
Formula I

In the above formula (I)
Y ¹ and Y ² are adjacent atoms in Het ¹ , which is independently selected from the group consisting of carbon and nitrogen;
k is 0, 1, 2 or 3;
Het ¹ is a divalent monocyclic 5 or 6 membered heteroaromatic radical having as ring members 1, 2 or 3 heteroatoms or heteroatom moieties selected from O, S, N and NR ^a , or O, S, 9 or 10 membered heteroaromatic radical having 1, 2, 3 or 4 heteroatoms or heteroatom moieties selected from N and NR ^a as ring members;
Het ² is a monocyclic 5 or 6 membered heteroaryl having as ring members 1, 2 or 3 heteroatoms or heteroatom moieties, in particular selected from O, S, N and NR ^1a ;
Cyc is in particular an optionally substituted monocyclic 5-membered or 6-membered heteroaryl or optionally substituted fused 8-membered, 9-membered or 10-membered bicyclic hetaryl;
Ar is optionally substituted phenylene or optionally substituted divalent 6-membered heteroaryl;
R is attached to a carbon atom of Het ^1, R is in particular halogen, C ₁ -C ₆ - alkyl, C ₂ -C ₆ - alkenyl, C ₂ -C ₆ - alkynyl, C ₁ -C ₆ - alkoxy , C ₁ -C ₆ -fluoroalkyl, C ₁ -C ₆ -fluoroalkoxy, C ₃ -C ₆ -cycloalkyl, and the like.

Description

NOVEL INHIBITOR COMPOUNDS OF PHOSPHODIESTERASE TYPE 10A OF PHOSPHODIESTERASE TYPE 10A [

The present invention provides a method of treating or inhibiting a medical disorder selected from a compound that is an inhibitor of phosphodiesterase type 10A, and thus neurological and psychotic disorders, alleviating the symptoms associated with the disorders, Lt; RTI ID = 0.0 > of the < / RTI >

Phosphodiesterase type 10A (hereinafter PDE10A) is a dual-substrate phosphodiesterase capable of converting cAMP to AMP and cGMP to GMP. PDE10A is very prominent in the mammalian brain. In other mammalian species as well as in rats, the mRNAs of PDE10A and PDE10A are highly expressed in GABA-functional medium spiny projection neurons (MSN) of striatal complexes (deltoid nucleus, septal nucleus and posterior tuberosity) Where production is controlled by the effect of PDE10A on cAMP and cGMP signaling cascades (cf. CJ Schmidt et al, The Journal of Pharmacology and Experimental Therapeutics 325 (2008) 681-690, A. Nishi, The Journal of Neuroscience 2008, 28, 10450-10471).

MSN expresses two functional classes of neurons: the D ₁ class expresses the D ₁ dopamine receptor, and the D ₂ class expresses the D ₂ dopamine receptor. The D ₁ class of neurons is part of the 'direct' striatal output pathway and functions extensively to promote behavioral responses. The D ₂ class of neurons is part of the 'indirect' striatal output pathway and functions to inhibit behavioral responses that compete with those promoted by the 'direct' pathway. PDE10A regulation of cAMP and / or cGMP signaling in the dendritic compartment of these neurons may be involved in filtering the cortical / sagittal input into the MSN. In addition, PDE10A may be involved in the regulation of GABA release in the black and pale nucleus (Seeger, TF et al. Brain Research, 2003, 985, 113-126). Inhibition of PDE10A leads to striatal activation and inhibition of behavior, e. G., Slowed gait, inhibition of the conditional avoidance response (CAR) and activity in the rat auditory gating model, which is an inhibitor of phosphodiesterase type 10A Suggesting a new class of antipsychotic agents.

The hypothesis about the physiological role of PDE10A and the therapeutic utility of PDE10A inhibitors is that the first widely-proffered pharmacological means compound for this purpose, papaverine (JA Siuciak et al. Loc. Cit.), Some are derived from the studies used. The PDE10A inhibitor papaverine appeared to be active in some antipsychotic models. Papaverine intensified the cataleptic effect of the D ₂ receptor antagonist haloperidol in rats, but did not induce hardening itself (WO 03/093499). Papaverine reduced hyperactivity in the rat induced by PCP, while the decrease in amphetamine-induced hyperactivity was minimal (WO 03/093499). These models suggest that PDE10A inhibition has the usual antipsychotic potential expected from theoretical considerations. However, papaverine has considerable limitations in that it has relatively poor efficacy and selectivity, and a very short exposure half-life after systemic administration. It has been shown that inhibition of PDE10A reverses subchronic PCP-induced deficiency at attentional set-shifting in rats suggesting that PDE10A inhibitors may alleviate schizophrenia-related cognitive deficits (Rodefer et al., Eur. J. Neurosci., 4 (2005) 1070-1076).

The discovery of a new class of PDE10A inhibitors with improved efficacy, selectivity and pharmacokinetic properties has provided an opportunity to further study the physiology of PDE10A and the potential therapeutic utility of inhibiting such enzymes. A new class of inhibitors are the MP-10 (PF-2545920: 2- {4- [1-methylpyridin-4-yl- 1 H- pyrazol-3- yl] phenoxymethyl} 10, i.e., 2 {4- [pyridin-4-yl-1- (2,2,2-trifluoroethyl) -1 H- pyrazol-3-yl] phenoxymethyl} -quinoline . These compounds provide a therapeutic approach to the treatment of schizophrenia (cf. C. Schmidt et al., Loc cit .; S.M. Grauer et al., Journal of Pharmacology and Experimental Therapeutics, fast forward DOI 10.1124 JPET 109.155994). Positive signals in the rodent model of schizophrenia include inhibition of conditional avoidance response (CAR), inhibition of hyperactivity caused by amphetamine-induced dopamine release or blockade of phencyclidine (PCP) mediated NMDA receptors, pharmacological ≪ / RTI > and antagonism of apomorphine-induced climbing. Taken together, this data suggests extensive inhibition of all three symptom groups (positive signs, negative signs & cognitive impairment) related to schizophrenia (cf. CJ Schmidt et al., Loc cit .; SM Grauer et al ., loc. cit).

In addition to schizophrenia, selective PDE10 inhibitors may have potential for the treatment of Huntington's disease (see SH Francis et al., Physiol. Rev., 91 (2011) 651-690) (F. Sotty et al., J. Neurochem., 109 (2009) 766-775). In addition, PDE10A inhibitors have been suggested to be useful in the treatment of obesity and non-insulin dependent diabetes mellitus (see WO 2005/120514, WO 2005/012485, Cantin et al, Bioorganic & Medicinal Chemistry Letters 17 2007) 2869-2873).

In summary, inhibitors of PDE10A provide a promising therapeutic approach to treat or prevent neurological and psychotic disorders, particularly schizophrenia and related disorders, including signs associated with schizophrenia, such as cognitive dysfunction.

Several classes of compounds that are inhibitors of PDE10A are described in the art and the latest group of compounds are:

Imidazo [1,5-a] pyrido [3,2-e] pyridazine and structurally related tricyclic imidazo [1,5-a] pyridazine- WO 2007/137819, 137820, WO 2009/068246, WO 2009/068320, WO 2009/070583, WO 2009/070584, WO 010/054260 and WO 2011/008597,

4-substituted phthalazine and quinazolines WO 2007/085954, WO 2007/022280, WO 2007/096743, WO 2007/103370, WO 2008/020302, WO 2008/006372 And WO 2009/036766;

4-Substituted < / RTI > Thinazolines - WO 2006/028957, WO 2007/098169, WO 2007/098214, WO 2007/103554, WO 2009/025823 and WO 2009/025839 [

Isoquinoline and isoquinolinone-WO < RTI ID = 0.0 > 2007/100880 < / RTI > and WO 2009/029214,

MP10 and MP10-like compounds: WO 2006/072828, WO 2008/001182 and WO 2008/004117; And

Benzodiazepine - see WO 2007/082546.

For further review, see also T. Chappie et al. Current Opinion in Drug Discovery & Development 12 (4), (2009) 458-467) and references cited therein.

Although some compounds of the prior art are known to effectively inhibit PDE10A with IC50 values of less than ₅₀ nM, compounds that inhibit PDE10A are still required. In particular, there is a continuing need for compounds having one of the following properties:

i. Selective inhibition of PDE10A, especially in comparison to inhibition of other phosphodiesterases such as PDE2, PDE3 or PDE4;

ii. Metabolic stability, in particular microbial stability, measured in vitro in liver microsomes from various species (e. G., Rats or humans) in human cells such as hepatocytes;

iii. Absolute inhibition or only low inhibition of the sheet chromium P450 (CYP) enzyme: Sheet chromium P450 (CYP) is the name for the super family (oxidase) of the heme protein with enzyme activity. They are also particularly important in the degradation (metabolism) of foreign substances such as drugs or xenobiotic in mammalian organisms. Important representatives of types and subtypes of CYP in the human body are CYP 1A2, CYP 2C9, CYP 2D6 and CYP 3A4. When CYP 3A4 inhibitors (e.g., grapefruit juice, cimetidine, erythromycin) are used contemporaneously with a medicinal substance degraded by these enzymes to compete for the same binding site for the enzyme, its degradation slows down, Thus, the effects and side effects of the administered drug can be undesirably promoted;

iv. Suitable water solubility (mg / ml);

v. Suitable pharmacokinetics (time course of concentration of a compound of the invention in plasma or tissue, e.g., brain). Pharmacokinetics can be described by the following parameters: half-life, distribution volume (l · kg ^-1 ), plasma clearance (l · h ^-1 · kg ^-1 ), AUC (area under the curve, The area (ng · h · l ^-1 ), oral bioavailability (AUC after oral administration and dose-normalized ratio of intravenous administration of AUC), so-called brain-plasma ratio Ratio of AUC in plasma);

vi. Compounds that block hERG channel blocking or only low blocking: the hERG channel can cause prolongation of the QT interval and thus lead to severe cardiac rhythm disturbances (e. g., so-called "ventricular tachycardia"). The potential for compounds to block hERG channels can be measured by a displacement assay using radiolabeled streptavidin described in the literature (G. J. Diaz et al., Journal of Pharmacological and Toxicological Methods , ≪ / RTI > 50 (2004), 187-199). A smaller IC50 in this dipetylated assay means greater potential for strong hERG blockade. In addition, blocking of the hERG channel can be measured by so-called whole-cell patch clamping by electrophysiology experiments on cells transfected with the hERG channel (GJ Diaz et al., Journal of Pharmacological and Toxicological Methods, 50 (2004), 187-199).

vii. The high free fraction in the brain, ie the fraction of compound bound to the protein, must be low.

viii. Low lipophilic.

BRIEF DESCRIPTION OF THE DRAWINGS

Thus, the present invention is based on the object of providing a compound that inhibits PDE10A at low concentrations.

In addition, the compound has a high selectivity for inhibition of at least one of the above-mentioned characteristics i to viii, in particular PDE10A, a high selectivity compared to other phosphodiesterases, for example, enhanced metabolic stability, Is intended to exhibit bacteriostatic stability, cytoplasmic stability or hepatocyte stability, low affinity for HERG receptors, low inhibition of sheet chromium P450 (CYP) enzyme, suitable water solubility and suitable pharmacokinetics.

These and further objects are achieved by compounds of formula (I) as defined below, their N-oxides, prodrugs, hydrates and tautomers and their pharmaceutically acceptable salts:

(I)

In the above formula (I)

Y ¹ and Y ² are adjacent atoms in Het ¹ , which are independently selected from the group consisting of carbon and nitrogen;

k is 0, 1, 2 or 3;

Het ¹ is a divalent monocyclic 5 or 6 membered heteroaromatic radical having as ring members 1, 2 or 3 heteroatoms or heteroatom moieties selected from O, S, N and NR ^a , or O , A divalent fused bicyclic 8-, 9- or 10-membered heteroaromatic radical having 1, 2, 3 or 4 heteroatoms or heteroatom moieties selected from S, N and NR ^a as ring members;

Het ² is

i. O, S, S = O, S (= O) _2, N, and saturated or partially unsaturated, 5-to 10-membered having from 1, 2 or 3 heteroatoms or heteroatom moiety selected from NR ^1a as ring members Monocyclic or heterobicyclic radicals,

ii. 5 or 6 membered heteroaryl having 1, 2 or 3 heteroatoms or heteroatom moieties selected from O, S, N and NR ^1a as ring members,

iii. 9 or 10-membered heteroaryl having 1, 2 or 3 heteroatoms or heteroatom moieties selected from O, S, N and NR ^1a as ring members,

iv. Phenyl

, ≪ / RTI >

Wherein Het ² may have 1, 2 or 3 radicals R ¹ ;

Cyc

i. Monocyclic 5 or 6 membered heteroaryl having 1 or 2 nitrogen atoms and any additional heteroatoms selected from O, S and N as ring members, which are unsubstituted or substituted by 1, 2, 3 or 4 Which may have the same or different substituents R < ² >),

ii. A fused 8-, 9- or 10-membered bicyclic hetaryl having one heteroatom selected from O, S and N and optionally one, two or three nitrogen atoms as ring members, wherein the fused bicyclic Hetaryl is unsubstituted or may have 1, 2, 3 or 4 identical or different substituents R < ² >),

iii. Phenyl having monocyclic hetaryl radicals having one or two nitrogen atoms and any further heteroatoms selected from O, S and N as ring members, which may be monocyclic hetaryl, in addition to one, two or three ^Which may have the same or different substituents R < ^2a >) and

iv. 2 or 3 heteroatoms or heteroatom moieties selected from O, S, S = O, S (= O) ₂ , N and NR ^1a as ring members and 1, 2 or 3 identical or different substituents R ^2b C ₅ -C ₈ and may have a-cyclic cycloalkyl or saturated or partially unsaturated 5- to 10-membered heterocyclic mono or bicyclic heteroaryl radical

≪ / RTI >

Ar is phenylene or divalent 6-membered hetaryl having 1, 2 or 3 nitrogen atoms as ring members, wherein the phenylene and the divalent 6-membered hetaryl are unsubstituted or substituted by 1, 2, 3 or 4 Have the same or different substituents R ³ ,

R is attached to a carbon atom of Het ^1, R is a ^{halogen, CN, NR 13 R 14,} C (O) NR 13 R 14, C 1 -C 6 - alkyl, C ₂ -C ₆ - alkenyl, C ₂ -C ₆ - alkynyl, trimethylsilyl, C ₁ -C ₆ - alkyl sulfanyl, C ₁ -C ₆ - alkylsulfonyl, fluorinated C ₁ -C ₆ - alkyl sulfanyl, fluorinated C ₁ -C ₆ - alkyl sulfonic C ₁ -C ₄ -alkyl-OR ¹¹ , C ₁ -C ₄ -alkyl-SR ¹² , C ₁ -C ₄ -alkyl-NR ¹³ R ¹⁴ , C ₁ -C ₆ -alkoxy, OC ₁ -C ₄ Alkyl-OR ¹¹ , OC ₁ -C ₄ -alkyl-SR ¹² , OC ₁ -C ₄ -alkyl-NR ¹³ R ¹⁴ , C ₂ -C ₆ -alkenyloxy, C ₁ -C ₆ -fluoroalkyl, Is selected from the group consisting of C ₁ -C ₆ -fluoroalkoxy, C ₃ -C ₆ -cycloalkyl and C ₃ -C ₆ -cycloalkyl-C ₁ -C ₄ -alkyl, wherein in said last two radicals Cycloalkyl moiety is unsubstituted, partially fluorinated or fully fluorinated, or is substituted with 1, 2 or 3 methyl groups;

R ^a is ^{hydrogen, C (O) NR 13 R} 14, C 1 -C 6 - alkyl, C ₂ -C ₆ - alkenyl, C ₂ -C ₆ - alkynyl, trimethylsilyl, C ₁ -C ₄ - alkyl, -OR ^11, C ₁ -C ₄ - alkyl, -SR ^12, C ₁ -C ₄ - alkyl, _{^{-NR 13 R 14, C 1 -C}} 6 - alkyl, fluoroalkyl, C ₁ -C ₆ - alkoxy, C ₃ fluoro -C ₆ - cycloalkyl, and C ₃ -C ₆ - cycloalkyl, -C ₁ -C ₄ - is selected from the group consisting of alkyl, where the last two radicals cycloalkyl moiety in is unsubstituted or substituted with a fluorinated part Or is fully fluorinated, or is substituted with 1, 2 or 3 methyl groups;

When attached to two radicals and R is or R is a radical with the radical R ^a, adjacent ring atoms, linear C ₃ -C ₅ -, and may form a alkanediyl, wherein one or two CH ₂ moiety T is C = O, O, S, S (= O), S (= O) can be replaced by a ₂ or NR ', where alkanediyl thing is optionally substituted with halogen, C ₁ -C ₄ - alkyl, C ₁ -C ₄ - fluoroalkyl, C ₁ -C ₄ - alkoxy and C ₁ -C ₄ - may have one or two radicals selected from alkoxy and fluoro;

R ¹ is attached to the carbon atom of Het ² and R ¹ is halogen, CN, NR ¹³ R ¹⁴ , C (O) NR ¹³ R ¹⁴ , C ₁ -C ₆ -alkyl, C ₂ -C ₆ -alkenyl, C ₂ -C ₆ - alkynyl, trimethylsilyl, C ₁ -C ₆ - alkyl sulfanyl, C ₁ -C ₆ - alkylsulfonyl, fluorinated C ₁ -C ₆ - alkyl sulfanyl, fluorinated C ₁ -C ₆ - alkylsulfonyl, C ₁ -C ₄ - alkyl, -OR ^11, C ₁ -C ₄ - alkyl, -SR ^12, C ₁ -C ₄ - alkyl, _{^{-NR 13 R 14, C 1 -C}} 6 - alkoxy, OC ₁ - C _{4-fluoro-alkyl} -OR ^11, OC ₁ -C ₄ - alkyl, -SR ^12, OC ₁ -C ₄ - alkyl, _{^{-NR 13 R 14, C 2 -C}} 6 - alkenyloxy, C ₁ -C ₆ Is selected from the group consisting of alkyl, C ₁ -C ₆ -fluoroalkoxy, C ₃ -C ₆ -cycloalkyl and C ₃ -C ₆ -cycloalkyl-C ₁ -C ₄ -alkyl, The cycloalkyl moiety in the radical is unsubstituted, partially fluorinated or fully fluorinated, or is substituted by 1, 2 or 3 methyl groups;

R ^1a is ^{hydrogen, C (O) NR 13 R} 14, C 1 -C 6 - alkyl, C ₂ -C ₆ - alkenyl, C ₂ -C ₆ - alkynyl, trimethylsilyl, C ₁ -C ₄ - alkyl, -OR ^11, C ₁ -C ₄ - alkyl, -SR ^12, C ₁ -C ₄ - alkyl, _{^{-NR 13 R 14, C 1 -C}} 6 - alkyl, fluoroalkyl, C ₁ -C ₆ - alkoxy, C ₃ fluoro -C ₆ - cycloalkyl, and C ₃ -C ₆ - cycloalkyl, -C ₁ -C ₄ - is selected from the group consisting of alkyl, where the last two radicals cycloalkyl moiety in is unsubstituted or substituted with a fluorinated part Or is fully fluorinated, or is substituted with 1, 2 or 3 methyl groups;

R ² is selected from the group consisting of halogen, C ₁ -C ₄ -alkyl, C ₁ -C ₄ -alkoxy, C ₁ -C ₄ -fluoroalkyl, C ₁ -C ₄ -fluoroalkoxy, C ₁ -C ₄ -alkoxy-C ₁ -C ₄ - alkoxy, C ₁ -C ₄ - alkoxy -C ₁ -C ₄ - alkyl, OH, hydroxy -C ₁ -C ₄ - alkyl, OC ₃ -C ₆ - cycloalkyl, benzyloxy, C ( _{O) O- (C 1 -C 4} - _{alkyl), O- (C 1 -C 4} - ^{_{alkyl) -CO 2 H, NR 23 R}} 24, C (O) NR 23 R 24, C 1 -C 4 - alkyl, ^{-NR 23 R 24, -NR 25 -C} (O) -NR 23 R 24, NR 25 -C (O) O- (C 1 -C 4 - _{^{alkyl), -NR 25 -SO 2 -R 22}} , Phenyl, CN, -SF ₅ , -OSF ₅ , -SO ₂ R ²² , -SR ²² , trimethylsilyl and C ₃ -C ₆ -cycloalkyl, wherein the cycloalkylmeyer in the last radical T is unsubstituted, partially fluorinated or fully fluorinated, substituted by 1, 2 or 3 methyl groups,

Two radicals R ² bonded to adjacent ring atoms may form a linear C ₃ -C ₅ -alkanediyl wherein one or two CH ₂ moieties may be replaced by C═O, O, S, S ( = O), S (= O) ₂ or NR 'where the alkanediyl is unsubstituted or substituted by halogen, C ₁ -C ₄ -alkyl, C ₁ -C ₄ -fluoroalkyl, C ₁ -C ₄ - alkoxy and C ₁ -C ₄ - may have one or two alkoxy radicals selected from fluoro;

R ^2a has one of the meanings given for R ² , or one radical R ^2a has one or two nitrogen atoms and a 5 membered ring with any further heteroatom selected from O, S and N as ring members and won or 6 may be a hat-aryl, wherein aryl is optionally substituted with het, halo, OH, C ₁ -C ₄ - alkyl, C ₁ -C ₄ - haloalkyl, C ₁ -C ₄ - alkoxy and C ₁ - C ₄ -haloalkoxy, < / RTI >

R ^2b is selected from the group consisting of halogen, C ₁ -C ₄ -alkyl, C ₁ -C ₄ -alkoxy, C ₁ -C ₄ -fluoroalkyl, C ₁ -C ₄ -fluoroalkoxy, C ₃ -C ₆ -cycloalkyl, C ₁ -C ₄ -alkoxy-C ₁ -C ₄ -alkoxy, C ₁ -C ₄ -alkoxy-C ₁ -C ₄ -alkyl, OH, hydroxy-C ₁ -C ₄ -alkyl, OC ₃ -C ₆ (C ₁ -C ₄ -alkyl), O- (C ₁ -C ₄ -alkyl) -CO ₂ H, NR ²³ R ²⁴ , C (O) NR ²³ R ^24, C ₁ -C ₄ - alkyl, ^{-NR 23 R 24, -NR 25 -C} (O) -NR 23 R 24, NR 25 -C (O) O- (C 1 -C 4 - alkyl), - NR ²⁵ -SO ₂ -R ²² , phenyl, CN, -SF ₅ , -OSF ₅ , -SO ₂ R ²² , -SR ²² and trimethylsilyl,

The two radicals R < ^2a > bonded to the adjacent ring atoms are fused benzene having one ring member selected from the group consisting of O, S, N or NR 'and optionally one or two further N-atoms as ring members Or fused 5 or 6 membered heteroaromatic ring wherein the fused benzene or heteroaromatic ring is unsubstituted or substituted by one or more substituents selected from the group consisting of halogen, OH, C ₁ -C ₄ -alkyl, C ₁ -C ₄ -fluoro 2, 3 or 4 radicals selected from haloalkyl, C ₁ -C ₄ -alkoxy and C ₁ -C ₄ -fluoroalkoxy;

R ³ is independently from each other selected from the group consisting of halogen, CN, NR ³³ R ³⁴ , C (O) NR ³³ R ³⁴ , C ₁ -C ₆ -alkyl, C ₂ -C ₆ -alkenyl, C ₂ -C ₆ -alkynyl trimethylsilyl, C ₁ -C ₆ - alkyl sulfanyl, C ₁ -C ₆ - alkylsulfonyl, fluorinated C ₁ -C ₆ - alkyl sulfanyl, fluorinated C ₁ -C ₆ - alkylsulfonyl, C ₁ -C _4-alkyl, -OR ^31, C ₁ -C ₄ - alkyl, -SR ^32, C ₁ -C ₄ - alkyl, _{^{-NR 33 R 34, C 1 -C}} 6 - alkoxy, OC ₁ -C ₄ - alkyl, -OR ^31, OC ₁ -C ₄ - alkyl, -SR ^32, OC ₁ -C ₄ - alkyl, _{^{-NR 33 R 34, C 2 -C}} 6 - alkenyloxy, C ₁ -C ₆ - alkyl, fluoroalkyl, C ₁ -C ₆ - C ₃ -C ₆ -cycloalkyl and C ₃ -C ₆ -cycloalkyl-C ₁ -C ₄ -alkyl, wherein the cycloalkyl moiety in the last two radicals is selected from the group consisting of Unsubstituted, partially fluorinated or fully fluorinated, or substituted with 1, 2 or 3 methyl groups;

R ^11, R ¹² are independently hydrogen, C ₁ -C ₄ together -alkyl, C ₁ -C ₄ - fluoroalkyl, C ₃ -C ₆ - cycloalkyl, and C ₃ -C ₆ - cycloalkyl, -C ₁ - C ₄ - is selected from the group consisting of alkyl, wherein, R ¹¹ is also C ₁ -C ₄ - alkylsulfonyl and C ₁ -C ₄ - alkylsulfonyl may imidazol fluoro;

R ^13, R ¹⁴ are independently hydrogen, C ₁ -C ₄ together -alkyl, C ₁ -C ₄ - fluoroalkyl, C ₃ -C ₆ - cycloalkyl, and C ₃ -C ₆ - cycloalkyl, -C ₁ - C ₄ -alkyl;

R ¹³ and R ¹⁴ together with the N atom to which they are attached form one, two or three further identical or different heteroatoms or heteroatom-containing groups selected from the group of O, N, S, SO and SO ₂ , 3-membered to 7-membered nitrogen heterocycle which may have 1, 2, 3, 4, 5 or 6 substituents which may be identical or different and are selected from C ₁ -C ₄ -alkyl and fluorine;

R ²¹ , R ²² , R ³¹ and R ³² have one of the meanings given for R ¹¹ , R ¹² ;

R ²³ , R ²⁴ , R ³³ and R ³⁴ have one of the meanings given for R ¹³ , R ¹⁴ ;

R ²⁵ is selected from the group consisting of hydrogen, C ₁ -C ₄ -alkyl, C ₁ -C ₄ -fluoroalkyl, C ₃ -C ₆ -cycloalkyl and C ₃ -C ₆ -cycloalkyl-C ₁ -C ₄ -alkyl Selected from the group;

R 'is selected from the group consisting of hydrogen, C ₁ -C ₄ -alkyl, C ₁ -C ₄ -fluoroalkyl, C ₃ -C ₆ -cycloalkyl and C ₃ -C ₆ -cycloalkyl-C ₁ -C ₄ -alkyl to be.

The present invention thus relates to the use of a compound of formula I, an N-oxide, a tautomer and a hydrate thereof, a pharmaceutically acceptable salt of a compound of formula I, a prodrug of a compound of formula I, , Prodrugs, tautomers or pharmaceutically acceptable salts of hydrates thereof. The present invention relates in particular to compounds of formula I and pharmaceutically acceptable salts thereof.

The present invention also relates to the use of a compound of formula (I), an N-oxide thereof, a tautomer thereof or a pharmaceutically acceptable salt thereof, for use in the treatment of a medical disorder selected from nervous system and psychotic disorders capable of being treated by modulation of phosphodiesterase type 10 And pharmaceutically acceptable salts of the compounds of formula (I), prodrugs of the compounds of formula (I) and pharmaceutically acceptable salts of said N-oxides, prodrugs, tautomers or hydrates of the compounds of formula (I) will be.

The use of a compound of formula I, a pharmaceutically acceptable salt thereof, an N-oxide thereof, a prodrug thereof, a hydrate thereof and a tautomer thereof, and a pharmaceutically acceptable salt of said N-oxide, a prodrug, a tautomer or a hydrate The salt efficiently inhibits PDE10A even at low concentrations. They are furthermore distinguished by a high selectivity for inhibition of PDE10A as compared to the inhibition of other phosphodiesterases such as PDE2, PDE3 or PDE4. The compounds of the present invention may additionally have one or more of the above-mentioned characteristics ii to viii.

Accordingly, the use of a compound of formula I, a pharmaceutically acceptable salt thereof, an N-oxide thereof, a prodrug thereof, a hydrate thereof and a tautomer thereof, and a pharmaceutically acceptable salt, solvate of such a N-oxide, a prodrug, a tautomer or a hydrate thereof Acceptable salts are particularly suitable for treating disorders and conditions in living organisms, particularly human life, that can be treated or inhibited by the inhibition of phosphodiesterase type 10A.

Thus, the present invention also relates to the use of a compound of formula (I), an N-oxide thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament, in particular a medicament suitable for the treatment of a disorder or condition treatable by inhibition of phosphodiesterase type 10A Its hydrates and pharmaceutically acceptable salts thereof, and the use of said pharmaceutically acceptable salts of said N-oxides, prodrugs, tautomers or hydrates.

The invention further relates to a medicament suitable for the treatment of a medicament, in particular a disorder or condition which can be treated by inhibition of phosphodiesterase type 10A. The medicament may comprise at least one compound of formula I as described herein, or an N-oxide, a tautomer, a hydrate or a prodrug of the compound of formula I, or a pharmaceutically acceptable salt of a compound of formula I, or Oxides, tautomers, hydrates or pharmaceutically acceptable salts of the prodrugs of the compounds of formula (I).

The present invention also relates to the use of compounds of formula I, especially IB, IB, which have ¹²³ I, in particular isotopic labels, in particular positron-emitting isotope labels, in particular ¹¹ C-labeled or ¹⁸ F- labeled or gamma- IA.a, IB.a, IA.a 'or IB.a'. These compounds are valuable diagnostic tools and can be used, for example, in positron emission tomography (PET) and single photon emission computed tomography (sPECT), respectively.

DETAILED DESCRIPTION OF THE INVENTION

The terms "compound of formula I" and "compound I" are used as synonyms.

The term "prodrug" refers to a compound that is metabolized in vivo with compound I of the present invention. Typical examples of prodrugs are described in CG Wermuth (editor): The Practice of Medicinal Chemistry, Academic Press, San Diego, 1996, pages 671-715. This includes, for example, phosphates, carbamates, amino acids, esters, amides, peptides, urea, and the like. Suitable prodrugs in the context of the present invention may be, for example, derivatives of these compounds I having OH or NH ₂ - groups, wherein the OH or NH ₂ - group is an ester / amide / peptide linkage form, that is OH or NH ₂ - one of the hydrogen atoms in the group C ₁ -C ₄ - alkyl carbonyl by a carbonyl group, e.g., acetyl, propionyl, n- propyl-carbonyl, isopropyl-carbonyl, is linked to the oxygen or nitrogen of the OH or NH ₂ -group by benzoyl, or via a carbonyl group of an amino acid, for example, by methyl, ethyl, n-butylcarbonyl or tert-butylcarbonyl (pivaloyl) For example, an acyl group derived from glycine, alanine, serine, phenylalanine or the like. Further suitable prodrugs, the OH- or NH _{2-alkyl-carbonyl-oxy-alkyl} carbonate or carbamate of a compound I having a group, in which, OH- or NH ₂ - one of the group of hydrogen atoms has the formula -C ( = O) -O-CHR ^p -OC (= O) -R ^q wherein R ^p and R ^q are independently of each other C ₁ -C ₄ -alkyl. Such carbonates and carbamates are described, for example, in J. Alexander, R. Cargill, SR Michelson, H. Schwam, J. Medicinal Chem. 1988, 31 (2), 318-322. These groups can then be removed under metabolic conditions, resulting in Compound I. Accordingly, the prodrugs and their pharmaceutically acceptable salts are also part of the present invention.

The term "pharmaceutically acceptable salt" refers to a cationic or anionic salt compound, wherein the counter ion is derived from a pharmaceutically acceptable non-toxic base or acid comprising an inorganic or organic base and an inorganic or organic acid do.

When the compound of formula (I) or a prodrug, tautomer, hydrate or N-oxide thereof is acidic, the salt may be prepared from a pharmaceutically acceptable non-toxic base including inorganic and organic bases. Salts derived from inorganic bases include salts wherein the counter ions are aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganese, manganese, potassium, sodium, zinc ions and the like. Particularly preferred are ammonium, calcium, magnesium, potassium and sodium ions. Salts derived from pharmaceutically acceptable organic non-toxic bases include, but are not limited to, primary, secondary and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, and basic ion exchange resins, But are not limited to, arginine, betaine, caffeine, choline, dibenzylethylene-diamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, But are not limited to, amino acids such as deuterium, glucamine, glucamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resin, procaine, purine, theobromine, , Tripropylamine, tromethamine, and the like.

When the compound of formula I or its prodrugs, tautomers, hydrates or N-oxides are basic, the salts may be prepared from pharmaceutically acceptable non-toxic acids including inorganic and organic acids. Such acids include but are not limited to acetic, trifluoroacetic, benzenesulfonic, benzoic, camphorsulfonic, citric, ethanesulfonic, fumaric, gluconic, glutamic, hydrobromic, Methanesulfonic acid, mucic acid, nitric acid, fumaric acid, pantothenic acid, phosphoric acid, succinic acid, sulfuric acid, tartaric acid, p-toluenesulfonic acid and the like. Particularly preferred are citric acid, hydrobromic acid, hydrochloric acid, maleic acid, phosphoric acid, sulfuric acid, fumaric acid and tartaric acid. As used herein, reference to a compound of formula (I) will be understood to include the inclusion of pharmaceutically acceptable salts.

The compounds of the present invention are mixtures of diastereoisomers, or mixtures of diastereoisomers rich in one of the two diastereomers, or essentially diastereomerically pure compounds (di> 90% diastereomeric excess) . The compound is preferably in the form of an essentially diastereomerically pure compound (diastereomeric excess (de)> 90%). In addition, the compounds of formula (I) of the present invention may be used as mixtures of enantiomers (e. G. As racemates), mixtures of enantiomers enriched in one of the two enantiomers, or mixtures of enantiomerically pure compounds (Enantiomeric excess (ee) > 90%). It is preferred to use enantiomerically pure or diastereomerically pure compounds.

In addition, the present invention (such as the one or more of the atoms, a stable isotope indicated in formula I, g., With hydrogen, deuterium, ¹² C is a ¹³ C, ¹⁴ N with a ¹⁵ N, ¹⁶ O is a ¹⁸ O ) Or an unstable, i.e. radioactive isotope (for example, ¹² C is replaced by ¹¹ C, ¹⁶ O is replaced by ¹⁵ O, and ¹⁹ F is replaced by ¹⁸ F), preferably a stable isotope, As defined herein, which is abundant in nature, in excess of the natural level. Of course, the compounds according to the invention contain more isotopes of each isotope than naturally occurring and are therefore present as compounds of the formula I anyway.

The compounds of formula I in solid form and their salts may exist in more than one crystal structure (polymorphism) and may also be present in the form of hydrates or other solvates. The present invention includes Compound I or salts thereof as well as any hydrates or any polymorphs of other solvates.

In the context of the present disclosure, the terms "alkyl", "alkenyl", "alkynyl", "alkoxy", "fluoroalkyl", "fluoroalkoxy", " Radicals derived from fluorinated radicals such as "hydroxylalkyl," "alkoxylalkyl," "alkoxy", " Alkoxy "," alkylsulfanyl "," alkylsulfonyl "," fluorinated alkylsulfanyl "," fluorinated alkylsulfonyl "," cycloalkylalkyl "denote a group of individual radicals. The groups of the noncyclic radicals "alkyl", "alkenyl", "alkynyl", "alkoxy", "fluoroalkyl", "fluoroalkoxy", "alkylene", "alkanediyl" And radicals derived therefrom are always selected from the group consisting of both unbranched and branched "alkyl", "alkenyl", "alkynyl", "alkoxy", "fluoroalkyl", "fluoroalkoxy", "alkyl Quot; and "alkandiyl ", respectively.

The prefix C _n -C _m - represents the number of carbon atoms in the hydrocarbon unit. Unless otherwise indicated, fluorinated substituents preferably have 1 to 5 identical or different fluorine atoms.

The term "halogen" refers in each case to fluorine, bromine, chlorine or iodine, in particular fluorine, chlorine or bromine.

The term " partially fluorinated or fully fluorinated "means that at least one, e.g., 1, 2, 3, 4, 5 or 6, or all of the hydrogen atoms of each moiety is replaced by a halogen atom, Lt; / RTI >

Examples of other meanings are:

Alkyl, and alkyl moieties in, for example, alkoxy, alkoxyalkyl, alkoxyalkoxyl, alkylsulfanyl, alkylsulfonyl: one or more C atoms, for example, 1 to 6 or 1 to 4 carbon atoms Saturated, straight or branched chain hydrocarbon radical. Examples of C ₁ -C ₄ -alkyl are methyl, ethyl, propyl, 1-methylethyl, n-butyl, 1-methylpropyl, 2-methylpropyl and 1,1-dimethylethyl. C ₁ -C ₆ -alkyl is, apart from those mentioned for C ₁ -C ₄ -alkyl, n-pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, 2,2- Methylpropyl, 1-methylpropyl, 3-methylpentyl, 4-methylpentyl, 1,1-dimethylbutyl, Dimethylbutyl, 1,3-dimethylbutyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl, 3,3-dimethylbutyl, 1-ethylbutyl, -Trimethylpropyl, 1,2,2-trimethylpropyl, 1-ethyl-1-methylpropyl and 1-ethyl-2-methylpropyl.

Fluoroalkyl moieties in fluoroalkyl, fluoroalkyl, fluorinated alkylsulfanyl, and fluorinated alkylsulfonyl, in which some or all of the hydrogen atoms are replaced by fluorine atoms, Alkyl radicals having 1 to 6 C atoms, often 1 to 4 C atoms, especially 1 or 2 C-atoms (C ₁ -C ₂ -fluoroalkyl), for example fluoromethyl, difluoro Methyl, trifluoromethyl, 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, pentafluoroethyl, 2-fluoro- 2-difluoro-1-methylethyl, 2,2-trifluoro-1-methylethyl, 2-fluoropropyl, 3-fluoropropyl, 2,2- Fluoropropyl, 3,3,3-trifluoropropyl, 2,3,3,3-pentafluoropropyl, heptafluoropropyl, 1- (fluoromethyl) -2-fluoroethyl, Butyl Nonafluorobutyl.

Cycloalkyl, and cycloalkyl moiety in, for example, cycloalkoxy, cycloalkyl-C ₁ -C ₄ -alkyl or cycloalkyl-C ₁ -C ₄ -alkoxy: three or more C atoms, for example, 3 , Monocyclic, saturated hydrocarbon groups having 4, 5, 6, 7 or 8 carbon ring members, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.

Fluorinated cycloalkyl and fluorinated cycloalkyl moieties in, for example, fluorinated cycloalkoxy or fluorinated cycloalkyl-C ₁ -C ₄ -alkyl: 3 or more C atoms, for example 3, 4, 5, 6, Monocyclic, saturated hydrocarbon group having 7 or 8 carbon ring members such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl, wherein at least one, for example 1, 2, 3 , 4, 5 or 6 or all hydrogen atoms are replaced by fluorine atoms, and examples include 1-fluorocyclopropyl, 2-fluorocyclopropyl, 2,2-difluorocyclopropyl, 1,2-difluoro Cyclopropyl, 2,3-difluorocyclopropyl, and the like).

Cycloalkylalkyl: a cycloalkyl radical as defined above linked through an alkylene group, in particular via a methylene, 1,1-ethylene or 1,2-ethylene group, such as cyclopropylmethyl, cyclobutylmethyl, Cyclohexylmethyl, cyclohexylmethyl, 1-cyclopropylethyl, 1-cyclobutylethyl, 1-cyclopentylethyl, 1-cyclohexylethyl, 2-cyclopropylethyl, 2-cyclobutylethyl, 2- 2-Cyclohexylethyl.

Fluorinated cycloalkylalkyl: Halogenated as defined above linked via an alkylene group, in particular via a methylene, 1,1-ethylene or 1,2-ethylene group, in particular a fluorinated cycloalkyl radical, for example 1-fluoro 2-fluorocyclopropylmethyl, 2-fluorocyclopropylmethyl, 2,2-difluorocyclopropylmethyl, 1,2-difluorocyclopropylmethyl, 2,3-difluorocyclopropylmethyl, 1- (1 (Fluorocyclopropyl) ethyl, 1- (2-fluorocyclopropyl) ethyl, 1- (2,2-difluorocyclopropyl) 2- (2-fluorocyclopropyl) ethyl, 2- (2-fluorocyclopropyl) ethyl, 2- Propyl) ethyl, 2- (1,2-difluorocyclopropyl) ethyl or 2- (2,3-difluorocyclopropyl) ethyl.

Alkenyl is a monounsaturated straight or branched chain hydrocarbon radical having at least two C atoms, for example from 2 to 8, in particular from 2 to 4, carbon atoms and one C = C-double bond at any position, For example C ₂ -C ₄ -alkenyl such as ethenyl, 1-propenyl, 2-propenyl, 1-methylethenyl, 1-butenyl, Methyl-1-propenyl, 2-methyl-1-propenyl, 1-methyl-2-propenyl and 2-methyl-

Alkynyl: a monounsaturated straight-chain or branched hydrocarbon radical having at least two C atoms, for example from 2 to 8, in particular from 2 to 6, carbon atoms and one C≡C-triple bond at any position, For example, C ₂ -C ₄ -alkenyl such as ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, Propinyl, 1-methyl-2-butynyl and 2-methyl-3-butynyl.

Alkoxy or alkoxy moieties such as alkoxyalkyl and alkoxyalkoxy:

An alkyl radical as defined above having 1 to 6 C atoms, in particular 1 to 4 C atoms, typically connected to the remainder of the molecule through the O atom, such as methoxy, ethoxy, n-propyl Propoxy, 1-methylethoxy, butoxy, 1-methylpropoxy, 2-methylpropoxy or 1,1-dimethylethoxy.

Fluoroalkoxy: alkoxy as mentioned above in which some or all of the hydrogen atoms of these groups are replaced by fluorine atoms, i. E. C ₁ -C ₄ -fluoroalkoxy, in particular C ₁ -C ₂ - Fluoroalkoxy, such as fluoromethoxy, difluoromethoxy, trifluoromethoxy, 2-fluoroethoxy, 2,2-difluoroethoxy, 2,2,2-trifluoroethoxy , Pentafluoroethoxy, 2-fluoropropoxy, 3-fluoropropoxy, 2,2-difluoropropoxy, 2,3-difluoropropoxy, 3,3,3-trifluoro Propoxy, 2,2,3,3,3-pentafluoropropoxy, heptafluoropropoxy, 1- (fluoromethyl) -2-fluoroethoxy, specifically fluoromethoxy, difluoromethoxy , Trifluoromethoxy, 2-fluoroethoxy or 2,2,2-trifluoroethoxy.

"Alkylsulfanyl ": an alkyl radical as defined above having usually 1 to 6 C atoms, especially 1 to 4 C atoms, connected to the remainder of the molecule through a sulfur atom, for example methylsulfanyl Ethylsulfanyl, n-propylsulfanyl, 1-methylethylsulfanyl, butylsulfanyl, 1-methylpropylsulfanyl, 2-methylpropylsulfanyl or 1,1-dimethylethylsulfanyl.

Fluorinated alkylsulfanyl: alkylsulfanyl as mentioned above in which some or all of the hydrogen atoms of these groups are replaced by fluorine atoms, i. E. For example C ₁ -C ₄ -fluoroalkylsulfanyl, especially C ₁ -C ₂ -fluoroalkylsulfanyl, such as fluoromethylsulfanyl, difluoromethylsulfanyl, trifluoromethylsulfanyl, 2-fluoroethylsulfanyl, 2,2-difluoro Ethylsulfanyl, 2,2,2-trifluoroethylsulfanyl, pentafluoroethylsulfanyl, 2-fluoropropylsulfanyl, 3-fluoropropylsulfanyl, 2,2-difluoropropylsulfanyl , 2,3-difluoropropylsulfanyl, 3,3,3-trifluoropropylsulfanyl, 2,2,3,3,3-pentafluoropropylsulfanyl, heptafluoropropylsulfanyl, 1 - (fluoromethyl) -2-fluoroethylsulfanyl, specifically fluoromethylsulfanyl, difluoromethylsulfanyl, trifluoro-methylsulfanyl, 2-fluoroethylsulfanyl Or 2,2,2-trifluoroethylsulfanyl.

"Alkylsulfonyl": an alkyl radical as defined above having 1 to 6 C atoms, typically 1 to 4 C atoms, typically connected to the remainder of the molecule through an S (O) ₂ moiety: For example, methylsulfonyl, ethylsulfonyl, n-propylsulfonyl, 1-methylethylsulfonyl, butylsulfonyl, 1-methylpropylsulfonyl, 2-methylpropylsulfonyl or 1,1-dimethylethylsulfonyl.

Fluorinated alkylsulfonyl: alkylsulfonyl as mentioned above in which some or all of the hydrogen atoms of these groups are replaced by fluorine atoms, i.e. C ₁ -C ₄ -fluoroalkylsulfonyl, especially C ₁ -C ₂ -fluoroalkylsulfonyl, such as fluoromethylsulfonyl, difluoromethylsulfonyl, trifluoromethylsulfonyl, 2-fluoroethylsulfonyl, 2,2-difluoro Ethylsulfonyl, 2,2,2-trifluoroethylsulfonyl, pentafluoroethylsulfonyl, 2-fluoropropylsulfonyl, 3-fluoropropylsulfonyl, 2,2-difluoropropylsulfonyl , 2,3-difluoropropylsulfonyl, 3,3,3-trifluoropropylsulfonyl, 2,2,3,3,3-pentafluoropropylsulfonyl, heptafluoropropylsulfonyl, 1 - (fluoromethyl) -2-fluoroethylsulfonyl, specifically fluoromethylsulfonyl, difluoromethylsulfonyl, trifluoromethylsulfonyl, 2-fluoroethylsulfonyl Or 2,2,2-trifluoroethylsulfonyl.

Hydroxyalkyl: An alkyl radical, usually having 1 to 4 C atoms, in which one hydrogen atom is replaced by an OH radical. Examples of these are CH ₂ -OH, 1-hydroxyethyl, 2-hydroxyethyl, 1 -hydroxypropyl, 2-hydroxypropyl, 1-methyl-1-hydroxyethyl, Ethyl, 3-hydroxypropyl, 2-hydroxybutyl, 3-hydroxybutyl, 4-hydroxybutyl, Methyl-1-hydroxypropyl and the like.

Alkoxyalkyl: An alkyl radical, usually having 1 to 4 C atoms, in which one hydrogen atom is replaced by an alkoxy radical, usually having 1 to 4 C atoms. Examples thereof include CH ₂ -OCH ₃ , CH ₂ -OC ₂ H ₅ , n-propoxymethyl, CH ₂ -OCH (CH ₃ ) ₂ , n-butoxymethyl, (1-methylpropoxy) - the methylpropoxy) _{methyl, CH 2 -OC (CH 3)} 3, 2- ( methoxy) ethyl, 2- (ethoxy) ethyl, 2- (n- propoxy) ethyl, 2- (1-methyl-1 2- (1-methylethoxy) ethyl, 2- (1-methylpropoxy) ethyl, 2- (n-propoxy) propyl, 2- (n-butoxy) propyl, 2- (n-propyl) (Methoxy) propyl, 3- (ethoxy) propyl, 3- (2-methylpropoxy) propyl, 2- propoxy) propyl, 3- (1-methylpropoxy) propyl, 3- (n-butoxy) 2- (ethoxy) butyl, 2- (n-propoxy) butyl, 2- (1-methylethoxy) propyl, 2- , 2- (n-butoxy Butyl, 2- (1-methylpropoxy) butyl, 2- (l, l-dimethylethoxy) butyl, 3- (methoxy) 3- (n-butoxy) butyl, 3- (1-methylpropoxy) butyl, 3- (n-propoxy) butyl, 3- 4- (ethoxy) butyl, 4- (n-propoxy) butyl, 4- (methoxy) 4- (1-methylethoxy) butyl, 4- (n-butoxy) butyl, 4- Butyl.

Alkoxyalkoxy: an alkoxyalkyl radical as defined above, usually having 1 to 4 C atoms in both alkoxy and alkyl moieties, connected to the remainder of the molecule through an O atom, examples of which include OCH ₂ -OCH ₃ , OCH ₂ -OC ₂ H ₅ , n-propoxymethoxy, OCH ₂ -OCH (CH ₃ ) ₂ , n-butoxymethoxy, (1-methylpropoxy) methoxy, _{ethoxy, OCH 2 -OC (CH 3)} 3, 2- ( methoxy) ethoxy, 2- (ethoxy) ethoxy, 2- (n- propoxy) ethoxy, 2- (1-methyl) Ethoxy, 2- (1-methyl-propoxy) ethoxy, 2- (2-methylpropoxy) Ethoxy and the like.

Each "alkylene" or "alkanediyl": typically 1-4 saturated hydrocarbon chain having carbon atoms, for example, methylene (-CH ₂ -), 1,2- ethylene (-CH ₂ CH ₂ -) , 1,1-ethanediyl (-CH (CH ₃ ) -), 1,2-propanediyl, 1,3-propanediyl, 1,4-butanediyl, Methyl-1,2-propanediyl, 2-methyl-1,3-propanediyl, 1-methyl-1,1-ethanediyl, 1-methyl-1,2-propanediyl and the like.

The saturated or partially unsaturated heterocyclic radical is usually a saturated or partially unsaturated, monocyclic heterocyclic radical having 3, 4, 5, 6, 7 or 8 ring atoms and usually 7, 8, 9 or 10 And includes a heterocyclic radical having a ring atom. In addition to carbon atoms, one, two or three ring atoms is a heteroatom moiety such as a cycloalkyl, or NR, S (= O) or S (= O) _2, such as N, S or O.

Examples of saturated heteromonocyclic radicals are in particular:

- Usually a saturated hetero monocyclic radical having 3, 4, 5, 6 or 7 ring atoms, wherein usually 1, 2 or 3 ring atoms are heteroatoms such as N, S or O other than carbon atoms as ring members to be). These include, for example:

C-linked ternary or quaternary saturated ring, for example,

2-oxiranyl, 2-oxetanyl, 3-oxetanyl, 2-aziridinyl, 3-thietanyl, 1-azetidinyl, 2-azetidinyl.

C-linked 5-membered saturated ring, e. G.

Tetrahydrofuran-2-yl, tetrahydrofuran-2-yl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydrothien- 3-yl, tetrahydroisoxazol-4-yl, tetrahydroisoxazol-5-yl, 1,2-oxathiolane- 3-yl, tetrahydroisothiazol-4-yl, tetrahydroisothiazol-4-yl, tetrahydroisothiazol- Tetrahydroimidazol-4-yl, tetrahydroimidazol-4-yl, tetrahydroimidazol-4-yl, tetrahydroimidazol- Tetrahydrothiazol-4-yl, tetrahydrothiazol-5-yl, tetrahydrothiazol-4-yl, tetrahydrothiazol-4-yl, tetrahydrothiazol- Dioxolane-2- , 1,3-dioxolan-4-yl, 1,3-oxathiolan-2-yl, Yl-1,3-dithiolan-4-yl, 1,3,2-dioxathiolan-4-yl.

C-linked 6-membered saturated ring, for example:

Yl, piperidin-3-yl, piperidin-4-yl, tetrahydrofuran-2-yl, tetrahydropyran-3- yl, tetrahydropyran- 3-yl, tetrahydrothiopyran-4-yl, 1,3-dioxan-2-yl, 1,3-dioxan- Yl, 1,3-dithiane-4-yl, 1,3-dithiane-5-yl, Dioxan-2-yl, 1,3-oxathian-4-yl, 1,3-oxathian-5-yl, 1,3- Oxathian-3-yl, 1,2-dithian-3-yl, 1,2-dithiane-4-yl , Hexahydropyridazin-3-yl, hexahydropyridazin-2-yl, hexahydropyrimidin-4-yl, hexahydropyrimidin-5-yl, 4-yl, tetrahydro-1,3-oxazin-5-yl, tetrahydro-1,3-oxazin-5-yl, tetrahydro- Tetrahydro-l, 3-thiazin-4-yl, tetrahydro-l, 3-thia Thiazin-2-yl, tetrahydro-1, 4-thiazin-3-yl, tetrahydro-1,3-thiazin-6-yl, tetrahydro- Tetrahydro-l, 4-oxazin-3-yl, tetrahydro-l, 4-yl, tetrahydro-l, 2-oxazin-5-yl, tetrahydro-l, 2-oxazin-6-yl.

N-linked 5-membered saturated rings, for example:

Tetrahydroimidazol-1-yl, tetrahydroimidazol-1-yl, tetrahydroimidazol-1-yl, tetrahydroimidazol- 3-yl, tetrahydrothiazol-3-yl.

N-linked 6-membered saturated rings, for example:

Pyridazin-1-yl, tetrahydro-1,3-oxazin-3-yl, tetrazol-1-yl, tetrahydropyrimidin-1-yl, Tetrahydro-1,4-thiazin-4-yl, tetrahydro-1,4-oxazin-4-yl, tetrahydro- -2 days.

Usually a saturated heterocyclic radical having 8, 9 or 10 ring atoms, wherein usually 1, 2 or 3 ring atoms are heteroatoms such as S or O other than carbon atoms as ring members or NH, N- Lt; / RTI > is a heteroatom moiety such as alkyl. These include, for example, 2-oxa-6-azaspiro- [3,4] octyl, 2- azabicyclo [2.2.1] heptyl, 5- azabicyclo [2.2.1] heptyl, Azabicyclo [3.2.1] octyl, 8-azabicyclo [3.2.1] octyl, 3,8-diazabicyclo [3.2.1] octyl, 2,3 , 4,4a, 5,6,7,7a-octahydro-1H-cyclopenta [b] pyridinyl, 2,3,3a, 4,5,6,7,7a-octahydro- 1,2,3,4,4a, 5,6,7,8,8a-decahydroquinolinyl and 1,2,3,4,4a, 5,6,7,8,8a-decahydroisoquin Nolinyl and NC ₁ -C ₄ -alkyl analogs;

- Usually 1, 2 or 3 ring atoms are heteroatoms such as N, S or O other than a carbon atom as a ring member, or an unsaturated heteroaromatic radical, usually having 4, 5, 6 or 7 ring atoms, . These include, for example:

C-linked 5-membered partially unsaturated rings, for example:

Dihydrofuran-2-yl, 2,5-dihydrofuran-3-yl, 2,3-dihydrofuran-2-yl, Dihydrofuran-2-yl, 2,3-dihydrothien-3-yl, 2,5-dihydrofuran- Dihydrothien-2-yl, 4,5-dihydrothien-3-yl, 2,3-dihydro- Dihydro-lH-pyrrol-2-yl, 2,5-dihydro-lH-pyrrole- 3-yl, 4,5-dihydro-1H-pyrrol-2-yl, 4,5-dihydro-1H- Dihydro-2H-pyrrol-3-yl, 3,4-dihydro-5H-pyrrol-2-yl, 3,4- Pyrazol-4-yl, 4,5-dihydro-1H-pyrazol-5-yl, 2,5-dihydro-1H Pyrazol-3-yl, 2,5-dihydro-1H-pyrazol-4-yl, 2,5-dihydro- Dihydro isoxazol-4-yl, 4,5-dihydro isoxazol-5-yl, 2,5-dihydro isoxazol- 3-yl, 2,3-dihydroisoxazol-4-yl, 2,5-dihydroisoxazol-5-yl, Dihydroisothiazol-4-yl, 4,5-dihydroisothiazol-4-yl, 4,5-dihydroisothiazol- 2,5-dihydroisothiazol-3-yl, 2,5-dihydroisothiazol-4-yl, 2,5-dihydroisothiazol- 5-yl, 2,3-dihydroisothiazol-5-yl, 2,3-dihydroisothiazol- Dihydro-1H-imidazol-2-yl, 4,5-dihydro-1H-imidazol-4-yl, 4,5- Dihydro-1H-imidazol-4-yl, 2,5-dihydro-1H-imidazol-5-yl, Dihydrooxazol-4-yl, 4,5-dihydrooxazol-2-yl, 4,5-dihydrooxazol-4 Dihydrooxazol-5-yl, 2,5-dihydrooxazol-2-yl, 2,5-dihydrooxazol-4-yl, 2,5-dihydrooxazol 2-yl, 2,3-dihydrooxazol-4-yl, 2,3-dihydrooxazol-5-yl, 4,5-dihydro Thiazol-2-yl, 4,5-dihydrothiazol-4-yl, 4,5-dihydrothiazol- Dihydrothiazol-2-yl, 2,3-dihydrothiazol-4-yl, 2,5-dihydrothiazol- 1,3-dioxol-4-yl, 1,3-dithiol-2-yl, 1,3-dithiol Yl, 1,3-oxathiol-2-yl, 1,3-oxathiol-4-yl,

C-linked 6-membered partially unsaturated ring, for example:

2,4-dihydropyran-4-yl, 2H-3,4-dihydropyran-5-yl, 2H- Yl, 2H-3,4-dihydrothiopyran-5-yl, 2H-3,4-dihydrothiopyran- 2H-3,4-dihydrothiopyran-4-yl, 2H-3,4-dihydrothiopyran- , 4-tetrahydropyridin-6-yl, 1,2,3,4-tetrahydropyridin-5-yl, 1,2,3,4-tetrahydropyridin- Tetrahydropyridin-3-yl, 1,2,3,4-tetrahydropyridin-2-yl, 2H-5,6-dihydropyran-2-yl, 2H- Yl, 2H-5,6-dihydropyran-6-yl, 2H-5,6-dihydropyran- 2H-5,6-dihydrothiopyran-3-yl, 2H-5,6-dihydrothiopyran-4-yl, 2H-5,6-dihydrothiopyran 5-yl, 2H-5,6-dihydrothiophe Tetrahydropyridin-2-yl, 1,2,5,6-tetrahydropyridin-3-yl, 1,2,5,6-tetrahydropyridin-4 Yl, 1,2,5,6-tetrahydropyridin-5-yl, 1,2,5,6-tetrahydropyridin-6-yl, 2,3,4,5-tetrahydropyridin- , 2,3,4,5-tetrahydropyridin-3-yl, 2,3,4,5-tetrahydropyridin-4-yl, 2,3,4,5-tetrahydropyridin- Pyran-4-yl, 4H-thiopyran-2-yl, 4H-pyran- Dihydropyridin-3-yl, 1,4-dihydropyridin-3-yl, 4H-thiopyran-4-yl, Pyran-2-yl, 2H-pyran-3-yl, 2H-pyran-4-yl, 2H- Thiopyran-4-yl, 2H-thiopyran-5-yl, 2H-thiopyran-6-yl, , 2-dihydropyridin-3-yl, 1,2-dihydropyridin-4 Yl, 3,4-dihydropyridin-3-yl, 3,4-dihydropyridin-2-yl, Dihydropyridin-4-yl, 3,4-dihydropyridin-5-yl, 3,4-dihydropyridin-6-yl, Dihydropyridin-3-yl, 2,5-dihydropyridin-4-yl, 2,5-dihydropyridin-5-yl, 2,5-dihydropyridin- 2-yl, 2,3-dihydropyridin-3-yl, 2,3-dihydropyridin-4-yl, 2,3-dihydropyridin- 2H-5,6-dihydro-1,2-oxazin-4-yl, 2H-5,6-dihydro- , 2H-5,6-dihydro-1,2-oxazin-6-yl, 2H-5,6-dihydro- Thiazin-4-yl, 2H-5,6-dihydro-1,2-thiazin-5-yl, 2H-5,6-dihydro- , 6-dihydro-1,2-thiazin-6-yl, 4H-5,6-dihydro- 4H-5,6-dihydro-1,2-oxazin-5-yl, 4H-5,6-dihydro- 4H-5,6-dihydro-1,2-thiazin-3-yl, 4H-5,6-dihydro-1,2-thia 4H-5,6-dihydro-1,2-thiazin-6-yl, 2H-3, 2H-3,6-dihydro-1,2-oxazin-4-yl, 2H-3,6-dihydro-1,2-ox 2H-3, 6-dihydro-1, 2-thiazin-3-yl, 2H-3,6-dihydro- 2H-3,6-dihydro-1,2-thiazin-5-yl, 2H-3,6-dihydro-1,2-thia 2-oxazin-4-yl, 2H-3, 4-dihydro- 2H-3,4-dihydro-1,2-oxazin-6-yl, 2H-3,4-dihydro-1,2-thia Thiazin-4-yl, 2H-3,4-dihydro-1,2-thiazin-5-yl, 2H- 4-di Thiazin-6-yl, 2,3,4,5-tetrahydropyridazin-3-yl, 2,3,4,5-tetrahydropyridazin-4-yl, 2,3 Tetrahydropyridazin-5-yl, 2,3,4,5-tetrahydropyridazin-6-yl, 3,4,5,6-tetrahydropyridazin-3-yl, Tetrahydropyridazin-4-yl, 1,2,5,6-tetrahydropyridazin-3-yl, 1,2,5,6-tetrahydropyridazin- , 2,5,6-tetrahydropyridazin-5-yl, 1,2,5,6-tetrahydropyridazin-6-yl, 1,2,3,6-tetrahydropyridazin- Tetrahydropyridazin-4-yl, 4H-5,6-dihydro-1,3-oxazin-2-yl, 4H-5,6-dihydro- 4H-5,6-dihydro-1,3-oxazin-5-yl, 4H-5,6-dihydro- Thiazin-2-yl, 4H-5,6-dihydro-1,3-thiazin-4-yl, 4H-5,6-dihydro- Thiazin-5-yl, 4H-5,6-dihydro-1,3-thiazin-6-yl, 3,4,5-6-tetrahydrofuran Yl, 3,4,5,6-tetrahydropyrimidin-4-yl, 3,4,5,6-tetrahydropyrimidin-5-yl, 3,4,5,6-tetrahydro Pyrimidin-6-yl, 1,2,3,4-tetrahydropyrazin-2-yl, 1,2,3,4-tetrahydropyrazin-5-yl, 1,2,3,4- Yl, 1,2,3,4-tetrahydropyrimidin-4-yl, 1,2,3,4-tetrahydropyrimidin-5-yl, 1,2,3,4-tetrahydro Thiazin-2-yl, 2,3-dihydro-1,4-thiazin-3-yl, 2,3-dihydro- Thiazin-5-yl, 2,3-dihydro-1,4-thiazin-6-yl, 2H-1,3- Yl, 2H-1,3-thiazin-2-yl, 2H-1,3- Thiazin-4-yl, 2H-1, 3-thiazin-5-yl, 2H- 4H-1,3-thiazin-2-yl, 4H-1,3-oxazin-5-yl, Thiazin-4-yl, 4H-1,3-thiazin-5-yl, 4H- Yl, 6H-1,3-oxazin-4-yl, 6H-1,3-oxazin-5-yl, , 6H-1,3-thiazin-2-yl, 6H-1,3-oxazin-4-yl, 6H- 2-yl, 2H-1,4-oxazin-3-yl, 2H-1,4-oxazin-5-yl, 2H- 2H-1,4-thiazin-2-yl, 2H-1,4-thiazin-3-yl, 2H- 4H-1,4-thiazin-2-yl, 4H-1,4-thiazin-6-yl, Dihydropyridazin-4-yl, 1,4-dihydropyridazin-5-yl, 1,4-dihydropyridazin-3-yl, Dihydropyridazin-6-yl, 1,4-dihydropyrazine-2-yl, 1,2-dihydropyrazine-2-yl, Dihydropyrimidin-2-yl, 1,4-dihydropyrimidin-4-yl, 1,4-dihydropyrimidin- Dihydropyrimidin-5-yl, 1,4-dihydropyrimidin-6-yl, 3,4-dihydropyrimidines 2-yl, 3,4-dihydro-4-yl, 3,4-dihydro-pyrimidin-5-yl or 3,4-dihydro-pyrimidin-6-yl.

N-linked 5-membered partially unsaturated rings, for example:

Dihydro-1H-pyrrol-1-yl, 2,5-dihydro-1H-pyrrol-1-yl, Dihydro-isoxazol-2-yl, 2,3-dihydroisoxazol-1-yl, 2,3-dihydro-isoxazol- 2-yl, 2,5-dihydroisothiazol-2-yl, 2,3-dihydroisoxazol-2-yl, 4,5-dihydro-1H-imidazol- Dihydro-1H-imidazol-1-yl, 2,3-dihydro-1H-imidazol-1-yl, 2,3-dihydrooxazol- -3 days.

N-linked 6-membered partially unsaturated rings, for example:

1,2,4-tetrahydropyridin-1-yl, 1,2,5,6-tetrahydropyridin-1-yl, 1,4-dihydropyridin- 2-yl, 2H-3, 5-dihydro-1, 2-thiazin-2-yl, Dihydro-1,2-oxazin-2-yl, 2H-3,6-dihydro-1,2-thiazin- 2H-3,4-dihydro-1,2-thiazin-2-yl, 2,3,4,5-tetrahydropyridazin-2-yl, 1,2,5,6 Tetrahydropyridazin-1-yl, 1,2,5,6-tetrahydropyridazin-2-yl, 1,2,3,6-tetrahydropyridazin-1-yl, Tetrahydropyrimidin-3-yl, 1,2,3,4-tetrahydropyrazin-1-yl, 1,2,3,4-tetrahydropyrimidin- Thiazin-4-yl, 2H-1,2-oxazin-2-yl, 2H-1,2-thia 4-thiopyridazin-1-yl, 1,4-dihydropyridazin-1-yl, Hydro-pyrazin-1-yl, 1,2-dihydro-pyrazin-1-yl, 1,4-dihydro-1-yl or 3,4-dihydro-pyrimidin-3-yl.

- Usually 1, 2 or 3 ring atoms are heteroatoms such as S or O other than carbon atoms as ring members or heteroatoms such as NH, < RTI ID = 0.0 >Lt; / RTI > is a heteroatom moiety such as N-alkyl). These include, for example, 2-oxa-6-azaspiro- [3,4] octyl, 2- azabicyclo [2.2.1] heptyl, 5- azabicyclo [2.2.1] heptyl,

2,5-diazabicyclo [2.2.1] heptyl, 3-azabicyclo [3.2.1] octyl,

Diazabicyclo [3.2.1] octyl, 2,3,4,4a, 5,6,7,7a-octahydro-lH-cyclopenta [3,2- b] pyridinyl, 2,3,3a, 4,5,6,7,7a-octahydro-lH-indolyl, 1,2,3,4,4a, 5,6,7,8,8a-deca Hydroquinolinyl and 1,2,3,4,4a, 5,6,7,8,8a-decahydroisoquinolinyl and NC ₁ -C ₄ -alkyl analogs;

Parts Examples of the unsaturated hetero-by-cycle is in particular a saturated or partially unsaturated by-carbonyl between the radical corresponding to the click radical (wherein one, two or three CH or CH ₂ moiety is N, NH, O, S, S (= O) or S (= O) ₂ , for example 2-oxa-6-azaspiro- [3,4] octyl, 2- azabicyclo [2.2.1] heptyl, Azabicyclo [3.2.1] heptyl, 2,5-diazabicyclo [2.2.1] heptyl, 3-azabicyclo [3.2.1] octyl, Diazabicyclo [3.2.1] octyl, dihydroindolyl, dihydroindolinyl, dihydroisoindolyl, dihydroquinolinyl, dihydroisoquinolinyl, chromenyl and chromanyl.

Heteroaryl: having usually 1, 2, 3 or 4 heteroatoms selected from O, S and N as ring members, in particular 1, 2, 3 or 4 nitrogen atoms or heteroatoms selected from oxygen and sulfur, Accordingly, a 5-membered or 6-membered aromatic heterocyclic radical (also referred to as a 5-membered or 6-membered monocyclic hetaryl) having 1 or 2 nitrogen atoms as a ring member other than a carbon atom as a ring member, and O, S 2, 3 or 4 heteroatoms selected from N, N and N as ring members, in particular 1, 2, 3 or 4 nitrogen atoms or a heteroatom selected from oxygen and sulfur and, An 8-, 9- or 10-membered aromatic heterocyclic radical having 1 or 2 nitrogen atoms as a ring member as a member (also an 8-, 9- or 10-membered bicyclic hetaryl FIG hereinafter): e.g.

2, or 3 or 4 nitrogen atoms or a C-linked 5-membered monocyclic hetaryl having a heteroatom selected from oxygen and sulfur, optionally having 1, 2 or 3 nitrogen atoms as ring members, For example:

2-thienyl, 3-thienyl, pyrrol-2-yl, pyrrol- , Isoxazol-4-yl, isoxazol-5-yl, isothiazol-3-yl, isothiazol- Yl, thiazol-5-yl, thiazol-5-yl, oxazol-4-yl, oxazol- Oxadiazol-4-yl, 1,2,3-oxadiazol-5-yl, 1,2,4-oxadiazol-3-yl, Yl, 1,2,3-thiadiazol-4-yl, 1,2,3-thiadiazol-5-yl, 1,2,4- Thiadiazol-3-yl, 1,2,4-thiadiazol-5-yl, 1,3,4-thiadiazolyl- , 2,4-triazol-3-yl, tetrazol-5-yl.

C-linked 6-membered monocyclic hetaryl having 1, 2 or 3 nitrogen atoms as ring members, for example:

Pyrimidin-4-yl, pyrimidin-4-yl, pyrimidin-4-yl, pyrimidin- Yl, 1, 2,4-triazin-3-yl, 1,2,4-triazin-5-yl, 2,4-triazin-6-yl, 1,2,4,5-tetrazin-3-yl.

An N-linked 5-membered heteroaromatic radical having 1, 2, 3 or 4 nitrogen atoms as ring members, for example:

Yl, imidazol-1-yl, 1,2,3-triazol-1-yl, 1,2,4-triazol-1-yl, tetrazole-1-yl, -Work.

A bicyclic 8-membered, 9-membered, 10-membered hetaryl, a hetaryl having one of the above-mentioned 5-or 6-membered heteroaromatic rings, and further aromatic carbocycles fused thereto or a 5- or 6-membered heterocycle , Such as fused benzene, thiophene, furan, pyrrole, pyrazole, imidazole, pyridine or pyrimidine ring. These bicyclic hetaryls are, for example, quinolinyl, isoquinolinyl, cinnolinyl, indolyl, indolizinyl, isoindolyl, indazolyl, benzofuryl, benzothienyl, benzo [b] thiazolyl , Imidazo [1,2-a] pyridin-2-yl, thieno [3,2-b] pyridin-5-yl, imidazo [ 1-b] -thiazol-6-yl and 1,2,4-triazolo [1,5-a] pyridin-2-yl.

In relation to their use as a PDE10A inhibitor, a variable Y ^1, Y ^2, Het ^1, k, R, Ar, Het ^2, Cyc, R, R ^a, R ^1, R ^1a, R ^2, R ^2a, R R ² , R ³ , R ¹¹ , R ¹² , R ¹³ , R ¹⁴ , R ²¹ , R ²² , R ²³ , R ²⁴ , R ²⁵ , R ³¹ , R ³² , R ³³ and R ³⁴ are preferably , Wherein they represent the specific configurations of the compounds of formula I, taking into account both themselves and in combination with at least one other or all:

In a particularly preferred group of embodiments, both Y ¹ and Y ² in Het ¹ are carbon atoms.

In another particular group of embodiments, ^one of Y ¹ and Y ² in Het ¹ is a carbon atom while the other of Y ¹ and Y ² is a nitrogen atom.

In particular, Het ¹ is a divalent monocyclic 5-membered ring having 1 heteroatom or heteroatom moiety selected from O, S and NR ^a as ring members and having 0, 1 or 2 additional nitrogen atoms as ring members Lt; / RTI > is a heteroaromatic radical.

In a particular group of embodiments, Het ¹ is a divalent monocyclic 5 membered heteroaromatic radical having one heteroatom moiety NR ^a and one additional nitrogen atom as ring members.

In another particular group of embodiments, Het ¹ is a divalent monocyclic 5 membered heteroaromatic radical having one heteroatom O or S and one additional nitrogen atom as ring members.

The variable k represents the number of substituents R on the carbon atom of the divalent radical Het ¹ , and k is in particular 0 or 1, in particular 0.

Het < ¹ > is in particular selected from the group consisting of 1- (R ^a ) -1 H-pyrazole-3,4-diyl, 1- (R ^a ) -1 H- pyrazole- , 1- (R ^a) -1H- imidazole-4,5-diyl, isoxazole-4,5-diyl, ^{isoxazole-3,4-diyl, 1- (R a) -1H-} 1,2, 1,3-diol, 1H-imidazole-1,5-diyl, 1H-imidazole-1,5-diyl, Triazole-1,2-diyl, wherein the above-mentioned radicals have k substituents R on the carbon atom of the divalent radical Het ¹ , k is as defined above, k is especially 0 or 1, especially 0.

The radical R, if present, is selected, in particular, from the group consisting of halogen, C ₁ -C ₄ -alkyl, C ₁ -C ₄ -alkoxy, C ₁ -C ₄ -fluoroalkyl and C ₁ -C ₄ -fluoroalkoxy Selected from the group consisting of fluorine, C ₁ -C ₂ -alkyl, C ₁ -C ₂ -alkoxy, C ₁ -C ₂ -fluoroalkyl and C ₁ -C ₂ -fluoroalkoxy.

R is ^a radical, when present, in particular hydrogen, C ₁ -C ₄ - alkyl, C ₁ -C ₄ - alkoxy, C ₁ -C ₄ - fluoroalkyl, and C ₁ -C ₄ - alkoxy group consisting of a fluoroalkyl And is especially selected from the group consisting of hydrogen, C ₁ -C ₄ -alkyl and C ₁ -C ₄ -fluoroalkyl.

Radicals R and R ^a, or the two radicals R are present in the case is coupled to the adjacent atoms in Het ^1, in particular a linear C ₃ -C ₅ - may form an alkanediyl also.

In the group of embodiments, Het ² is

i. O, S, S = O, S (= O) _2, N, and saturated or partially one, two or three hetero atoms or hetero atom moiety selected from NR ^1a having as ring members unsaturated 5-to 10-membered monocyclic Cyclic or heterobicyclic radicals,

ii. 5 or 6 membered heteroaryl having 1, 2 or 3 heteroatoms or heteroatom moieties selected from O, S, N and NR ^1a as ring members,

iii. Is selected from bicyclic 8-, 9- or 10-membered hetaryl having 1, 2 or 3 heteroatoms or heteroatom moieties selected from O, S, N and NR ^1a as ring members.

In particular, the moiety formed by Het1 and Het2 (hereinafter also referred to as a moiety of the formula Het1 / 2)

Het1 / 2q, Het1 / 2p and Het1 / 2q, in particular from the radicals Het1 / 2a and Het1 / 2q, especially the radicals Het1 / 2a, Het1 / 2d, Het1 / 2g, Selected:

The radicals R ^a in the formulas Het 1 / 2a to Het 1/2 q, when present, are as defined above and the radical R ^b , when present, is hydrogen or has one of the meanings given above for R. Het1 / 2f, Het1 / 2l, Het1 / 2m, Het1 / 2n, in the group having two radicals R ^b as Het1 / 2o and Het1 / 2p, the radical R ^b may be the same or different. The radical R ^b is in particular selected from the group consisting of hydrogen, halogen, C ₁ -C ₄ -alkyl, C ₁ -C ₄ -alkoxy, C ₁ -C ₄ -fluoroalkyl and C ₁ -C ₄ -fluoroalkoxy , Especially hydrogen, fluorine, C ₁ -C ₂ -alkyl, C ₁ -C ₂ -alkoxy, C ₁ -C ₂ -fluoroalkyl and C ₁ -C ₂ -fluoroalkoxy. Specifically, R ^b is hydrogen.

The radicals R ^a in the formulas Het 1 / 2a to Het 1 / 2q, when present, are in particular hydrogen, C ₁ -C ₄ -alkyl, C ₁ -C ₄ -alkoxy, C ₁ -C ₄ -fluoroalkyl and C ₁ - C ₄ -fluoroalkoxy and is especially selected from the group consisting of hydrogen, C ₁ -C ₄ -alkyl and C ₁ -C ₄ -fluoroalkyl.

In the formulas Het1 / 2a, Het1 / 2d, Het1 / 2g and Het1 / 2h, the radicals R ^b and R ^a can also form especially linear C ₃ -C ₅ -alkanediyl.

Formula Het1 / 2f, in Het1 / 2m, Het1 / 2n and Het1 / 2p, the two radicals R ^b in particular linear C ₃ -C ₅ - can also form alkanediyl.

Very particular aspect of the invention is the moiety Het1 / 2 a moiety of the formula Het1 / 2a, where, R ^a are as defined above, especially hydrogen, C ₁ -C ₄ - alkyl, C ₁ -C ₄ - alkoxy , C ₁ -C ₄ -fluoroalkyl and C ₁ -C ₄ -fluoroalkoxy, especially selected from the group consisting of C ₁ -C ₄ -alkyl and C ₁ -C ₄ -fluoroalkyl And R ^b is as defined above and is in particular hydrogen, halogen, C ₁ -C ₄ -alkyl, C ₁ -C ₄ -alkoxy, C ₁ -C ₄ -fluoroalkyl and C ₁ -C ₄ -fluoroalkoxy And more particularly selected from the group consisting of hydrogen, fluorine, C ₁ -C ₂ -alkyl, C ₁ -C ₂ -alkoxy, C ₁ -C ₂ -fluoroalkyl and C ₁ -C ₂ -fluoroalkoxy 0.0 > I < / RTI > Particularly in the formula Het1 / 2a, R < ^{b &} gt ^; is hydrogen.

Very particular further aspect of the present invention, Het1 moiety / 2 is a moiety of the formula Het1 / 2q, where, R ^a are as defined above, especially hydrogen, C ₁ -C ₄ - alkyl, C ₁ -C ₄ -Alkoxy, C ₁ -C ₄ -fluoroalkyl and C ₁ -C ₄ -fluoroalkoxy and is especially selected from the group consisting of C ₁ -C ₄ -alkyl and C ₁ -C ₄ -fluoroalkyl R ^b is as defined above and is in particular selected from the group consisting of hydrogen, halogen, C ₁ -C ₄ -alkyl, C ₁ -C ₄ -alkoxy, C ₁ -C ₄ -fluoroalkyl and C ₁ -C ₄ -fluoro a is selected from the group consisting of alkoxy, more particularly hydrogen, fluorine, C ₁ -C ₂ -alkyl, C ₁ -C ₂ - alkoxy, C ₁ -C ₂ - alkoxy, fluoro-alkyl, and C ₁ -C ₂ fluoroalkyl Lt; RTI ID = 0.0 > I < / RTI > Particularly in the formula Het1 / 2q, R < ^{b &} gt ^; is hydrogen.

A particular aspect of the invention relates to compounds of formula I, wherein Ar is a radical of the formula Ar-1:

[Chemical formula Ar-1]

In the above formula (Ar-1)

X ¹ is N or CR ^x1 ;

X ² is N or CR ^x2 ;

X ³ is N or CR ^{x 3} ;

X ⁴ is N or CR ^x4 ;

Provided that 0, 1 or 2 of X ¹ , X ² , X ³ and X ⁴ is N;

Wherein R ^x1 , R ^x2 , R ^x3 , R ^x4 are, independently of each other, hydrogen or have one of the meanings given for R ³ .

R ³ is, if present, in particular halogen, C ₁ -C ₄ -alkyl, C ₁ -C ₄ - from the group consisting of alkoxy, fluoro-alkyl, fluoro C ₁ -C ₄ -alkoxy and C ₁ -C ₄ Selected from the group consisting of fluorine, C ₁ -C ₂ -alkyl, C ₁ -C ₂ -fluoroalkyl, C ₁ -C ₂ -alkoxy and C ₁ -C ₂ -fluoroalkoxy. Thus, R ^x1 , R ^x2 , R ^x3 and R ^x4 are, independently of one another, especially hydrogen, halogen, C ₁ -C ₄ -alkyl, C ₁ -C ₄ -fluoroalkyl, C ₁ -C ₄ -alkoxy and C ₁ -C ₄ -fluoroalkoxy, especially hydrogen, fluorine, C ₁ -C ₂ -alkyl, C ₁ -C ₂ -fluoroalkyl, C ₁ -C ₂ -alkoxy and C ₁ -C ₂ -fluoroalkoxy, C ₂ -fluoroalkoxy. ≪ / RTI > At least two of the radicals R ^x1 , R ^x2 , R ^x3 and R ^x4 are hydrogen and in particular at least three or all of the radicals R ^x1 , R ^x2 , R ^x3 and R ^x4 are hydrogen.

A more particular group of embodiments relates to compounds of formula I, wherein Ar is a radical Ar-1, wherein X ¹ is CR ^x1 , X ² is CR ^x2 , X ³ is CR ^x3 , and X ⁴ is CR ^x4 . A more particular group of embodiments are those wherein Ar is a radical Ar-1 wherein X ¹ is CR ^x1 , X ² is CR ^x2 , X ³ is CR ^x3 , X ⁴ is CR ^x4 , wherein R ^x1 , At least three of R ^x2 , R ^x3 and R ^x4 are hydrogen and one or less of R ^x1 , R ^x2 , R ^x3 and R ^x4 is a radical R ³ as defined above. A particular group of embodiments relates to compounds of formula I, wherein Ar is a radical Ar-1, wherein each X ¹ , X ² , X ³ and X ⁴ is CH.

Special group of embodiments was Ar is a radical Ar-1, Het1 moiety / 2 is a radical Het1 / 2a, where, R ^b is hydrogen relates to compounds of formula I. These compounds can be described by the following formula (IA).

(I-A)

Thus, certain groups of embodiments is Cyc, X ^1, X ^2, X ^3, X ^4, Het ² and R ^a are as is defined above, Cyc, X ^1, X ^2, X ^3, X ^4, Het ² and R ^a , especially N-oxides, prodrugs, tautomers and hydrates thereof, and pharmaceutically acceptable salts of compounds of formula I, prodrugs thereof, tautomers thereof, And hydrates.

Another particular group of embodiments Ar is a radical Ar-1 and the moiety Het1 / 2 is a radical Het1 / 2q, where, R ^b is hydrogen relates to compounds of formula I. These compounds may be described by the following formula (IB).

(I-B)

Thus, certain groups of embodiments is Cyc, X ^1, X ^2, X ^3, X ^4, Het ² and R ^a are as is defined above, Cyc, X ^1, X ^2, X ^3, X ^4, Het ² and R ^a , especially N-oxide, prodrug, tautomer and hydrate thereof, and pharmaceutically acceptable salts of compounds of formula I, prodrugs thereof, tautomers thereof, And hydrates.

In formulas IA and IB, the variable X ¹ is in particular CR ^x1 , X ² in particular CR ^x2 , X ³ in particular in CR ^x3 and X ⁴ in particular in CR ^x4 , where R ^x1 , R ^x2 , R ^x3 and R ^x4 is as defined above wherein at least three of R ^x1 , R ^x2 , R ^x3 and R ^x4 are hydrogen and one or more of R ^x1 , R ^x2 , R ^x3 and R ^x4 are as defined above Is a radical R < ³ >

A specific group of embodiments relates to compounds of formula IA wherein each of X ¹ , X ² , X ³ and X ⁴ is CH. These compounds may be described by the following formula IA. A.

[Formula I-A]

Therefore, the specific group of embodiments is Cyc, Het ² and R ^a is as defined above Cyc, Het ² and R ^a is in particular a compound of formula IA.a having provided the particular or specific meanings, their N- oxides, Pro Solvates, tautomers and hydrates, and the pharmaceutically acceptable salts, the prodrugs, the tautomers and the hydrates thereof of the compounds of formula (I).

Another particular group of embodiments pertains to compounds of formula IB wherein each of X ¹ , X ² , X ³ and X ⁴ is CH. These compounds can be described by the formula (IB.a) below.

[Formula I-B.a]

Thus, another group of specific embodiments is Cyc, Het ² and R ^a are the same as defined Cyc, Het ² and R ^a is in particular provided the compound of formula or specific IB.a having specific meanings, their N- oxides , Prodrugs, tautomers and hydrates, and pharmaceutically acceptable salts of the compounds of formula (I), their prodrugs, tautomers and hydrates.

In Formulas I, IA, IB, IA.a and IB.a, Het ² is especially phenyl or phenyl optionally substituted with one heteroatom selected from O, S and N as a ring member and also with one or two additional heteroatoms Membered monocyclic hetaryl, wherein the phenyl and the 5-or 6-membered hetaryl are unsubstituted or have, independently of each other, 1, 2 or 3 radicals R < ^{1 &} gt ;. Het ² is more particularly selected from the group consisting of phenyl, oxazolyl, isoxazolyl, furyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyrimidinyl and pyridazinyl, Radicals are unsubstituted or may have 1, 2 or 3 radicals R < ¹ > as defined above. More particularly, in formulas IA and IA.a, the variable Het ² is selected from the group consisting of 4-pyrazolyl, 3-pyrazolyl, 4-pyridyl, 4-pyrimidinyl, 5-pyrimidinyl and 4-pyridazinyl , Wherein the above-mentioned radicals are unsubstituted or may have one or two radicals R < ¹ > as defined above.

In certain embodiments of compounds of formulas I, IA, IB, IA.a and IB.a, Het ² is an unsubstituted 6-membered hetaryl, for example pyridyl, pyrimidinyl or pyridazinyl.

In a further particular embodiment of the compounds of formulas I, IA, IB, IA.a and IB.a, Het ² is phenyl substituted by one radical R ¹ , wherein R ¹ is as defined above, _{CN, NH 2, NH-C} 1 -C 2 - alkyl, N (C ₁ -C ₂ - alkyl) _2, C ₁ -C ₂ - alkyl, C ₁ -C ₂ - alkoxy, C ₁ -C ₂ - fluoro Fluoroalkoxy and C ₁ -C ₂ -fluoroalkoxy and is especially selected from the group consisting of fluorine, chlorine, CN, methyl, difluoromethyl, trifluoromethyl, methoxy, difluoromethoxy, trifluoromethoxy and It is selected from the group consisting of NH _2.

In a further particular embodiment of the compounds of formula I, IA, IB, IA.a and IB.a, Het ² is an unsubstituted 6-membered hetaryl, for example pyridyl, pyrimidinyl or pyridazinyl.

In a specific group of embodiments of the compounds of formula I, IA, IB, IA.a and IB.a, Het ² is 4-pyridyl.

A very specific group of embodiments relates to compounds of formula IA wherein each of X ¹ , X ² , X ³ and X ⁴ is CH and Het ² is 4-pyridyl. These compounds may be represented by the following formula IA.

[Formula I-A.a '

Thus, a very specific group of embodiments is Cyc and R ^a are the same as defined above and R ^a is Cyc, and in particular to the specific compounds of the formula or IA.a 'having specific meanings, their N- oxides, prodrugs provided in , Tautomers and hydrates, and the pharmaceutically acceptable salts of the compounds of formula (I), their prodrugs, tautomers and hydrates.

Another very specific group of embodiments relates to compounds of formula IB wherein each of X ¹ , X ² , X ³ and X ⁴ is CH and Het ² is 4-pyridyl. These compounds can be described by the following general formula IB.a '.

[Formula I-B.a '

Thus, a very specific group of embodiments is Cyc and R ^a are the same as defined above and R ^a is Cyc, and in particular to the specific compounds of the formula or IB.a 'having specific meanings, their N- oxides, prodrugs provided in , Tautomers and hydrates, and the pharmaceutically acceptable salts of the compounds of formula (I), their prodrugs, tautomers and hydrates.

In the formulas I, IA, IB, IA.a, IB.a, IA.a 'and IB.a', the radical Cyc is in particular a C-linked 5-membered or 6-membered ring having 1 or 2 nitrogen atoms as ring members And a C-linked 9-membered or 10-membered fused ring having one or two nitrogen atoms as ring members and optionally having a further heteroatom selected from O, S and N as ring members Wherein the monocyclic hetaryl, benzofuryl and bicyclic hetaryl may be unsubstituted or have 1, 2, 3, or 4 substituents R < ² > have. More particularly, Cyc is a C-linked 5-or 6-membered monocyclic hetaryl having 1 or 2 nitrogen atoms as ring members, and a C-linked, fused 9-membered or 10-membered bicyclic hetaryl, monocyclic hetaryl and bicyclic hetaryl may be unsubstituted or may have 1, 2, 3 or 4 substituents R < ² > . In particular, Cyc is unsubstituted or has 1 or 2 substituents R < ^{2 &} gt ;.

The radicals Cyc in the formulas I, IA, IB, IA.a, IB.a, IA.a 'and IB.a' are, in particular, at least one imino-nitrogen located at a position adjacent to the carbon atom bonded to the triple bond As a ring member. More particularly, Cyc has at least one imino-nitrogen located at a position adjacent to the carbon atom bonded to the triple bond as a ring member and is a C-linked 5-membered or 6-membered ring having 1 or 2 nitrogen atoms as ring members Monocyclic hetaryl, and C-linked fused 9-membered or 10-membered bicyclic hetaryl having 1 or 2 nitrogen atoms as a ring member, wherein the monocyclic hetaryl and bicycle Cl-Hetaryl may be unsubstituted or may have 1, 2, 3 or 4 substituents R < ² >. In particular, Cyc is unsubstituted or has 1 or 2 substituents R < ^{2 &} gt ;.

In this context, R ² is, if present, in particular halogen, C ₁ -C ₄ - alkyl, C ₁ -C ₂ - alkyl, fluoroalkyl, C ₁ -C ₄ - alkoxy, C ₁ -C ₂ - alkoxy fluorine, C ₃ -C ₆ -cycloalkyl and fluorinated C ₃ -C ₆ -cycloalkyl. In this regard, R < ² > is especially fluorine, chlorine, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, methoxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy, cyclopropyl and fluorinated cyclo Profile.

In particular, in the formulas I, IA, IB, IA.a, IB.a, IA.a 'and IB.a', the radicals Cyc are 2-pyridyl, 2- pyrimidinyl, 4- pyrimidinyl, Thiazolyl, 2-quinolinyl, 3-isoquinolinyl, 2-thiazolyl, 2-thiazolyl, Naphthyridin-2-yl, benzothiazol-1-yl, benzoxazol-1-yl, benzimidazolyl, Pyridin-2-yl, pyrrolo [2,3-b] pyridin-6-yl, 3,2-b] pyridin-5-yl, imidazo- [2,1-b] -thiazol-6-yl and 1,2,4-triazolo [1,5- a] pyridin- is selected from the group consisting of, wherein the aforementioned radicals are as defined above, particularly halogen, C ₁ -C ₄ - alkyl, C ₁ -C ₂ - alkyl, fluoroalkyl, C ₁ -C ₄ - alkoxy, C ₁ - C ₂ - fluorinated alkoxy, C ₆ -C ₃ - C ₃ -C ₆ cycloalkyl, and fluorinated - a cycloalkyl the 2 or 3 groups selected from the group consisting of fluorine, chlorine, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, methoxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy, the methyl group of the optionally substituted cyclopropyl, and fluorinated cyclopropyl one, two or three radicals R ² are selected from the group consisting of may have.

In addition, the variables R ', R ¹¹ , R ¹² , R ¹³ , R ¹⁴ , R ²¹ , R ²² , R ²³ , R ²⁴ , R ²⁵ , R ³¹ , R ³² , R ³³ and R ³⁴ , Regardless of the occurrence, in connection with Formulas I, IA, IB, IA.a, IB.a, IA.a 'and IB.a' and in connection with each of the above-mentioned aspects, groups of embodiments and particularly preferred embodiments And has one of the following meanings:

R ¹¹ , R ²¹ and R ³¹ are, independently of one another, especially hydrogen, C ₁ -C ₂ -alkyl, C ₁ -C ₂ -fluoroalkyl, methyl, ethyl, difluoromethyl, trifluoromethyl, cyclo Propyl, cyclobutyl or cyclopropylmethyl.

R ¹² , R ²² and R ³² are, independently of one another, especially C ₁ -C ₄ -alkyl or C ₁ -C ₄ -fluoroalkyl, in particular methyl, ethyl, difluoromethyl or trifluoromethyl.

R ¹³ , R ²³ and R ³³ are, independently of one another, especially hydrogen or C ₁ -C ₄ -alkyl, especially hydrogen, methyl, ethyl, propyl or isopropyl.

R ¹⁴ , R ²⁴ and R ³⁴ are, independently of one another, especially hydrogen or C ₁ -C ₄ -alkyl, especially hydrogen, methyl, ethyl, propyl or isopropyl.

R ¹³ and R ¹⁴ , R ²³ and R ²⁴ , R ³³ and R ³⁴ , together with the nitrogen atom to which they are bonded, form pyrrolidin-1-yl, piperidin- Yl, thiomorpholin-4-yl, piperazin-1-yl and 4-methylpiperazin-1-yl, wherein six The above-mentioned heterocyclic radicals may have 1, 2, 3 or 4 substituents selected from methyl and fluorine.

R ²⁵ is especially hydrogen or C ₁ -C ₄ -alkyl, especially hydrogen, methyl, ethyl or propyl or isopropyl.

R 'is particularly hydrogen or C ₁ -C ₄ - alkyl, in particular hydrogen, methyl, ethyl or propyl or isopropyl.

Certain embodiments of the present invention are directed to compounds of formula I, N-oxides, prodrugs, hydrates and tautomers thereof, and pharmaceutically acceptable salts thereof, wherein the compounds of formula I are selected from the group consisting of:

4- (1-methyl-3- (4 - ((1-methyl -1 H-imidazol-ethynyl-5-yl)) phenyl) -1 H-pyrazol-4-yl) pyridine,

2 - ((4- (1-methyl-4- (pyridin-4-yl) -1 H-ethynyl-pyrazol-3-yl) phenyl)) pyridine,

5-methyl-2 - ((4- (1-methyl-4- (pyridin-4-yl) -1 H-ethynyl-pyrazol-3-yl) phenyl)) pyridine,

4- (1-methyl-3- (4 - ((1-propyl -1 H-pyrazol-4-yl) ethynyl) phenyl) -1 H-pyrazol-4-yl) pyridine,

5-fluoro-2 - ((4- (1-methyl-4- (pyridin-4-yl) -1 H-ethynyl-pyrazol-3-yl) phenyl)) pyridine,

3-methyl-2 - ((4- (1-methyl-4- (pyridin-4-yl) -1 H-ethynyl-pyrazol-3-yl) phenyl)) pyridine,

4- (1-methyl-3- (4 - ((1-methyl -1 H-imidazol-ethynyl-2-yl)) phenyl) -1 H-pyrazol-4-yl) pyridine,

4-methyl-2 - ((4- (1-methyl-4- (pyridin-4-yl) -1 H-ethynyl-pyrazol-3-yl) phenyl)) pyridine,

2-methyl-6 - ((4- (1-methyl-4- (pyridin-4-yl) -1 H-ethynyl-pyrazol-3-yl) phenyl)) pyridine,

4- (1-methyl-3- (4 - ((1-methyl -1 H-pyrazol-4-yl) ethynyl) phenyl) -1 H-pyrazol-4-yl) pyridine,

4- (3- (4 - (( 1 H - pyrazol-4-yl) ethynyl) phenyl) -1-methyl -1 H - pyrazol-4-yl) pyridine,

2 - ((4- (1 -methyl-4- (pyridin-4-yl) -lH- pyrazol-3- yl) phenyl) ethynyl) quinoline,

2- [2- [4- [1 -methyl-4- (4-pyridyl) pyrazol-3-yl] phenyl] ethynyl] -1,5-naphthyridine,

Yl] phenyl] ethynyl] imidazo [l, 2-a] pyridine,

LH-pyrrolo [2,3-b] pyridine, l- (2-methylsulfanyl)

Methyl-2- [2- [4- [1 -methyl-4- (4-pyridyl) pyrazol-3-yl] phenyl] ethynyl] quinoline,

2- [2- [4- [1 -methyl-4- (4-pyridyl) pyrazol-3-yl] phenyl] ethynyl] thiazole,

2- [2- [4- [1 -methyl-4- (4-pyridyl) pyrazol-3-yl] phenyl] ethynyl] quinoxaline,

Pyridyl) -2- (4-pyridyl) -6,7-dihydro-5H-pyrrolo [1,2- a] imidazole,

Yl] phenyl] ethynyl] pyridine, 2-methoxy-6- [2- [4- [

3-yl] phenyl] ethynyl] pyridine, < / RTI >

4- [1-methyl-3- [4- (2-phenylethynyl) phenyl] pyrazol-

Pyridyl) ethynyl] phenyl] -2- (4-pyridyl) -6,7-dihydro-5H-pyrrolo [1,2- a ] Imidazole,

5- [1-methyl-3- [4- [2- (6-methyl-2-pyridyl) ethynyl] phenyl] pyrazol-

Yl] phenyl] ethynyl] pyridine, 2-methyl-6- [2- [4- [

Yl] phenyl] ethynyl] pyridine, 2-methyl-6- [2- [4- [

Yl] phenyl] ethynyl] -pyridine, 2-methyl-6- [2- [4- [

4- [1-methyl-3- [4- [2- (6-methyl-2-pyridyl) ethynyl] phenyl] pyrazol-

Yl] phenyl] ethynyl] pyridine, < RTI ID = 0.0 > 2-

Yl] phenyl] ethynyl] -6-methyl-pyridine, < / RTI >

Yl] phenyl] ethynyl] -6-methyl-pyridine and (2-methoxyphenyl)

2- [2- [2-Methoxy-4- [1 -methyl-4- (4-pyridyl) pyrazol-3-yl] phenyl] ethynyl] -6-methyl-pyridine.

The compounds of formula I, IA, IA.a, IA.a ', IB, IB.a and IB.a' of the present invention and the starting materials used to prepare them can be used in standard organic chemistry studies, : Houben-Weyl, "Methoden der Organischen Chemie", Thieme-Verlag, Stuttgart, Jerry March "Advanced Organic Chemistry", 5 th edition, Wiley & Sons and the literature cited therein, and R. Larock, "Comprehensive Organic Transformations", 2 < ^nd > edition, Weinheim, 1999 and the literature cited therein. The compounds of formula I of the present invention are advantageously prepared by the methods described below and / or in the Examples section.

A suitable method for preparing compounds of formula (I) wherein Y < ¹ > is a carbon atom comprises the reaction of a compound of formula (II) as shown in Scheme 1 with a compound Het ² -M.

Scheme 1:

In Scheme 1, the variables k, R, Y ² , Ar, Het ¹ , Het ² and Cyc are as defined above. L is selected from the group consisting of halogens such as chlorine, bromine or iodine, alkylsulfonates such as methylsulfonate, phenylsulfonate, alkylphenylsulfonates such as tosylate and perfluoroalkylsulfonate, For example, it is a suitable leaving group, including triplet, pentaplate, heptaplate or nonaplate. M is a metal or metal bonded organometallic group such as Li, MgHal, ZnHal wherein Hal is Cl, Br or I, a group Sn (R ^Sn ) ₃ , where R ^Sn is C ₁ -C ₆ -alkyl or C ₃ -C ₆ -cycloalkyl) or phenyl. M is also a radical B (OR ^B1 ) (OR ^B2 ), where R ^B1 and R ^B2 are independently of each other hydrogen or C ₁ -C ₄ -alkyl or R ^B1 and R ^B2 together are C ₂ Form a -C ₆ -alkanediyl moiety, such as ethane-1,2-diyl, propane-1,3-diyl or 1,1,2,2-tetramethylethane-1,2-diyl .

The reaction of the compound M-Het ² with the compound of the formula II can be carried out analogously to the known coupling reaction in the presence of a suitable transition metal catalyst, in particular a palladium catalyst. Typical reaction conditions include, but are not limited to, steel coupling and related reactions (see Stille et al. Angew. Chem. Int. Ed. Engl. 1986, 25, 508; J. Eluguero et al .; Synthesis 1997 , 5 , 563-566) Coupling (see A. Suzuki et al, Chem. Rev. 1995 , 95, 2457-2483, N. Zhe et al .; J. Med. Chem. 2005 , 48 (5) , 1569-1609; Young et al J. Med. Chem. 2004 , 47 (6), 1547-1552; C. Slee et al., Bioorg. Med. Chem. Lett 2001 , 9 , 3243-3253, T. Zhang et al., Tetrahedron Lett 52 (2011), 311-313, S. Bourrain et al., Synlett. 5 (2004), 795-798).

A suitable method for preparing compounds of formula (I) wherein Y < ¹ > is a nitrogen atom comprises the reaction of a compound of formula (II ') with a compound Het ² -LG as shown in scheme 2.

Scheme 2:

In Scheme 2, variables k, R, Y ² , Ar, Het ¹ , Het ² and Cyc are as defined above. LG is selected from the group consisting of halogens such as chlorine, bromine or iodine, alkylsulfonates such as methylsulfonate, phenylsulfonate, alkylphenylsulfonates such as tosylate and perfluoroalkylsulfonate, For example, it is a suitable leaving group, including triplet, pentaplate, heptaplate or nonaplate. The reaction of the compound of formula (IIa) with the compound Het ² -LG is typically carried out in the presence of a transition metal catalyst such as palladium catalyst in terms of Buchwald-Hartwig reaction. Suitable palladium catalysts include, for example, tris- (dibenzylideneacetone) dipalladium (0) (Pd ₂ (dba) ₃ ), [1,1- bis (diphenylphosphino) ferrocene] dichloropalladium a (PdCl ₂ (dppf)) or palladium acetate (Pd (OAc) _2). The reaction may be carried out in the presence of a tri (substituted) phosphine such as triarylphosphine, for example triphenylphosphine, tritolylphosphine or 2,2'-bis (diphenyl-phosphino) -1,1 (Tri-butyl) phosphine or tris (cyclohexylphosphine), or dicyclohexyl (triphenylphosphine), for example, - (2 ', 4', 6'-tri-iso-propyl-biphenyl-2-yl) -phosphane (X-Phos). Typically, the reaction is carried out in the presence of a base, for example an alkaline alkoxide, earth alkali alkoxide, alkaline carbonate or alkaline carbonate, for example sodium tertiary-butoxide or cesium carbonate. Suitable transition metal catalysts are also copper (I) compounds, such as copper (I) iodide. Advantageously, the reaction of the compound of formula (II ') with Het ² -LG is then carried out in the presence of a diamine ligand. Suitable diamine ligands are 1,10-phenanthroline, trans-N, N'-dimethylcyclohexane-1,2-diamine or trans 1,2-cyclohexanediamine. Typically, the reaction is carried out in the presence of a base, for example an alkaline carbonate such as cesium carbonate or potassium carbonate.

Compounds of formula I may also be prepared by alkyne coupling as shown in scheme 3:

Scheme 3:

In Scheme 3, variables k, R, Y ² , Ar, Het ¹ , Het ² and Cyc are as defined above. Lg is selected from the group consisting of halogens such as chlorine, bromine or iodine, alkylsulfonates such as methylsulfonate, phenylsulfonate, alkylphenylsulfonates such as tosylate and perfluoroalkylsulfonate, For example, it is a suitable leaving group, including triplet, pentaplate, heptaplate or nonaplate.

The reaction of a compound of formula (III) with a compound of formula (IV) can be carried out in the presence of a suitable transition metal catalyst, in particular a palladium catalyst, for example analogously to known alkene coupling reactions in the presence of Sonogashira coupling. Typical reaction conditions are described, for example, in Prabakaran, K .; Nawaz Khan F .; Sung Jin J .; Tetahedron Lett. 52 ( 2011 ) 2566-2570) or in the Examples.

Suitable methods for preparing compounds of formula (I) wherein Y < ² > is a carbon atom include the reaction of a compound of formula (V) with a compound of formula (VI) as shown in Scheme 4.

Scheme 4:

In Scheme 4, the variables k, R, Y ² , Ar, Het ¹ , Het ² and Cyc are as defined above. L is selected from the group consisting of halogens such as chlorine, bromine or iodine, alkylsulfonates such as methylsulfonate, phenylsulfonate, alkylphenylsulfonates such as tosylate and perfluoroalkylsulfonate, For example, it is a suitable leaving group including triplet, pentaplate, heptaplate or nonaplate. M is a metal or metal bonded organometallic group such as Li, MgHal, ZnHal wherein Hal is Cl, Br or I, a group Sn (R ^Sn ) ₃ , where R ^Sn is C ₁ -C ₆ -alkyl or C ₃ -C ₆ -cycloalkyl) or phenyl. M also ^{B (OR B1) (OR B2} ) may be a radical, where, R ^B1 and R ^B2 are, independently, hydrogen or C ₁ -C ₄ together - alkyl, R ^B1 and R ^B2 are together C ₂ Form a -C ₆ -alkanediyl moiety, such as ethane-1,2-diyl, propane-1,3-diyl or 1,1,2,2-tetramethylethane-1,2-diyl . The reaction conditions are described for Reaction Scheme 1.

Compounds of formula II, II ', III, IV, V and VI are known or may be prepared analogously to the methods described in the examples below.

Compounds of formula II can be prepared analogously to the process shown in Scheme 3 by reaction of an alkyne of formula IV with a compound of formula V followed by the introduction of a leaving group L, for example by halogenation at Hetl.

Similarly, a compound of formula (II ') can be prepared by reaction of an alkyne of formula (IV) with a compound of formula (V'), wherein Sg is hydrogen or an N-protecting group, followed by optional deprotection, .

[Chemical Formula V ']

N-oxides of the compounds of formula I can be prepared, for example, by reacting a compound of formula I with an organic peracid, for example metachloropiperbenzoic acid or 3-chloroperbenzoic acid (Journal of Medicinal Chemistry 38 (11), 1892- 1903 (1995), WO 03/64572; Or an inorganic oxidizing agent; For example, by treatment with hydrogen peroxide (Journal of Heterocyclic Chemistry 18 (7), 1305-1308 (1981)] or Oxone (Journal of the American Chemical Society 123 (25), 5962-5973 Can be prepared from compounds of formula I according to conventional oxidation methods. The oxidation may result in a pure mono-N-oxide or a mixture of different N-oxides (which can be separated by conventional methods such as chromatography).

The reaction is typically carried out in an aprotic organic solvent such as a substituted amide, lactam and urea; For example, dimethylformamide, dimethylacetamide, N-methylpyrrolidone, tetramethylurea, cyclic ethers; For example, dioxane, tetrahydrofuran, halogenated hydrocarbons; For example, dichloromethane and mixtures thereof, as well as C ₁ -C ₆ -alkanol and / or water and mixtures thereof.

The reactions described above will normally be carried out in a temperature range of -10 ° C to 100 ° C, depending on the reactivity of the compounds used.

The reaction mixture is worked up in the customary manner, for example by mixing with water, separating the phases and, if appropriate, purifying the crude product by chromatography. The intermediates and final products are, in some cases, produced in the form of a colorless or light brown viscous oil which is either not volatile or is purified under reduced pressure and at an appropriate elevated temperature. When the intermediate and the final product are obtained as solids, the purification can also take place on recrystallization or digestion.

Due to its ability to inhibit PDE10A at low concentrations, the compounds of formula (I), their N-oxides, their hydrates, their tautomers and their prodrugs and their pharmaceutically acceptable salts are useful as phosphodiesterase type Lt; RTI ID = 0.0 > 10A. ≪ / RTI > The terms " treating "and" treating "in the context of the present invention refer to the curative treatment of a disease or disorder, the treatment of a symptom associated with the disease or disorder, Alleviation of the associated condition or symptom, and prophylactic treatment, i.e., treatment to reduce the risk of a disease or disorder.

Neurological and psychiatric disorders or conditions that can be treated by inhibition of PDE10A, including curative treatment, inhibition or alleviation and prevention, include CNS disorders, particularly cognitive dysfunctions associated with schizophrenia, depression, bipolar disorder, schizophrenia, , Huntington ' s disease (Huntington ' s disease), anxiety and substance-related disorders, particularly substance use disorders, and substance abuse conditions associated with substance withdrawal. Disorders or conditions that can be treated by inhibition of PDE10A, including curative treatment, inhibition or alleviation and prevention, also include the treatment of dietary induced obesity.

Accordingly, the present invention provides a compound of formula I, an N-oxide thereof, a hydrate thereof, a tautomer thereof and a prodrug thereof, and a pharmaceutically acceptable salt thereof, for the treatment of a disorder or condition treatable by inhibition of phosphodiesterase type 10A, That is, the present invention relates to the curative treatment of such a disease or disorder, the inhibition of such disease or disorder, the alleviation of the symptoms associated with such disease or disorder, and the treatment of such a disease or disorder To the use of such compounds to reduce risk.

The present invention also relates to a method for the treatment of a medical disorder selected from nervous system and psychotic disorders which can be treated by inhibition of phosphodiesterase type 10A, said method comprising administering a compound of formula (I), an N-oxide thereof, To a mammal in need of such treatment, an effective amount of at least one compound selected from the group consisting of its hydrates, its tautomers, its prodrugs, and the pharmaceutically acceptable salts thereof.

The invention particularly relates to:

Methods for treating, inhibiting, alleviating or reducing the risk of schizophrenia in mammals;

Methods for treating, inhibiting, alleviating or reducing the risk of cognitive disorders associated with schizophrenia in mammals;

A method for treating, inhibiting, alleviating or reducing the risk of depression in a mammal;

A method for treating, inhibiting, alleviating or reducing the risk of bipolar disorder in a mammal;

A method for treating or alleviating a symptom associated with a substance use disorder in a mammal;

A method for treating or alleviating the symptoms associated with dietary-induced obesity in mammals;

A method for treating, inhibiting, alleviating or reducing the risk of cognitive disorders associated with Alzheimer's disease in a mammal;

A method for treating, inhibiting, alleviating or reducing the risk of the behavioral signs of Alzheimer's disease;

A method for treating, inhibiting, alleviating or reducing the risk of anxiety in mammals;

To a method for treating, inhibiting, alleviating or reducing the risk of Huntington's disease in a mammal comprising administering to said mammal a compound of formula I, an N-oxide thereof, a hydrate thereof, a tautomer thereof, Comprising administering to a mammal in need of such treatment an effective amount of at least one compound selected from the group of pharmaceutically acceptable salts.

A subject to be treated by the method of the present invention is generally a mammal, preferably a male or female, that requires inhibition of PDE10A. The terms "effective amount" and "therapeutically effective amount" refer to the amount of a compound that will elicit the biological or medical response of a tissue, system, animal or human being sought by a researcher, veterinarian, physician or other clinician. One of ordinary skill in the art will recognize that an effective amount of a compound of the present invention can affect neurological and psychiatric disorders by treating a patient currently suffering from a disorder or prophylactically treating a patient suffering from the disorder. The terms " treating "and" treating ", as used herein, are intended to encompass all types of disorders that may slow, interfere with, block, inhibit or stop the progression of the disorders described herein, As well as prophylactic treatment of the conditions referred to in particular in patients susceptible to such diseases or disorders. The term "composition" as used herein is intended to encompass a product comprising the specified ingredients in the stated amounts, as well as any product that results, directly or indirectly, from the combination of the specified ingredients in the stated amounts. This term is intended to encompass a product comprising the active ingredient (s) and the inert ingredient (s) that make up the carrier in association with the pharmaceutical composition, as well as from the combination, complexation or aggregation of any two or more ingredients, Or from any other type of reaction or interaction of one or more of the components. Accordingly, the pharmaceutical compositions of the present invention include any composition made by admixing a compound of the present invention with a pharmaceutically acceptable carrier. By "pharmaceutically acceptable" it is meant that the carrier, diluent or excipient must be miscible with the other ingredients of the formulation and not deleterious to its receptor.

The term "administering" and / or "administering" a compound should be understood to mean providing a compound of the invention or a prodrug of a compound of the invention to an individual in need of treatment.

A preferred embodiment of the present invention relates to a method of treating schizophrenia comprising administering an effective amount of at least one compound selected from the group consisting of a compound of formula I, an N-oxide thereof, a hydrate thereof, a tautomer thereof, a prodrug thereof and a pharmaceutically acceptable salt thereof, ≪ / RTI > to a patient suffering from schizophrenia.

In another preferred embodiment, the present invention relates to a pharmaceutical composition comprising an effective amount of at least one compound selected from the group consisting of a compound of formula I, an N-oxide thereof, a hydrate thereof, a tautomer thereof, a prodrug thereof and a pharmaceutically acceptable salt thereof, To a patient in need of such cognitive disorder therapy. ≪ RTI ID = 0.0 > [0002] < / RTI >

Currently, the fourth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) (1994, American Psychiatric Association, Washington, DC) provides diagnostic tools including schizophrenia and other psychotic disorders do. These include disorders with psychotic signs as limiting characteristics. Term psychosis refers to small delusions, significant hallucinations, disorganized speech, confused or strained behavior. The disorder is selected from the group consisting of edema, confusion, tension, undifferentiated and residual schizophrenia, schizophreniform disorder, schizoaffective disorder, delusional disorder, short term psychotic disorder, , Substance-induced psychotic disorders, and psychotic disorders not otherwise specified. Skilled artisans will recognize that there are alternative nomenclature, disease taxonomy and classification systems for nervous and psychotic disorders, and in particular schizophrenia, and that these systems evolve with medical development. Thus, the term "schizophrenia" is intended to include similar disorders described in other diagnostic data.

In another preferred embodiment, the present invention relates to a method for the preparation of a medicament for the manufacture of a medicament for the treatment or prophylaxis of an inflammatory disease, comprising administering an effective amount of at least one compound selected from the group consisting of a compound of formula (I), an N-oxide thereof, a hydrate thereof, a tautomer thereof, Comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof.

In another preferred embodiment, the present invention provides an effective amount of at least one compound selected from the group consisting of a compound of formula I, an N-oxide thereof, a hydrate thereof, a tautomer thereof, a prodrug thereof and a pharmaceutically acceptable salt thereof, To a patient in need thereof. ≪ Desc / Clms Page number 2 > Currently, the fourth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) (1994, American Psychiatric Association, Washington, D.C.) provides diagnostic tools including anxiety and related disorders. These include, but are not limited to, panic disorder with or without agoraphobia, agoraphobia without history of panic disorder, specific phobias, social phobia, obsessive compulsive disorder, post-traumatic stress disorder, acute stress disorder, generalized anxiety disorder, Substance-induced anxiety disorder and anxiety disorder not otherwise specified. The term "anxiety " as used herein includes the treatment of anxiety disorders and related disorders as described in DSM-IV. Skilled artisans will recognize that there are alternative nomenclature, disease taxonomy and classification systems for nervous and psychotic disorders, and in particular anxiety, and that these systems evolve along with medical development. Thus, the term "anxiety" is intended to include similar disorders described in other diagnostic data.

In another preferred embodiment, the present invention provides a method of treating depression, comprising administering an effective amount of at least one compound selected from the group consisting of a compound of formula I, an N-oxide thereof, a hydrate thereof, a tautomer thereof, a prodrug thereof and a pharmaceutically acceptable salt thereof, To a patient in need thereof. ≪ Desc / Clms Page number 2 > Currently, the fourth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) (1994, American Psychiatric Association, Washington, D.C.) provides diagnostic tools including depression and related disorders. Depressive disorders include, for example, a single episode or recurrent major depressive disorder and depressive disorder, depressive and neurotic depression; Melancholic depression including anorexia, weight loss, insomnia and early morning weather and psychomotor retardation; Atypical depression (or reactive depression), including increased appetite, hypersomnia, psychomotor retardation or irritability, anxiety and phobia; Seasonal affective disorder; Or bipolar disorder or bipolar disorder, for example Type I bipolar disorder, Type II bipolar disorder, and cyclical disorders. The term "depression " as used herein includes the treatment of depressive disorders and related disorders as described in DSM-1V.

In another preferred embodiment, the present invention relates to a method for the preparation of a medicament for the manufacture of a medicament for the treatment or prophylaxis of an inflammatory disease, comprising administering an effective amount of at least one compound selected from the group consisting of a compound of formula (I), an N-oxide thereof, a hydrate thereof, a tautomer thereof, Related disorders, particularly substance abuse, substance abuse, substance tolerance and substance abstinence, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula . Currently, the fourth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) (1994, American Psychiatric Association, Washington, DC) describes drug abuse abuse (including alcohol), drug side effects, ≪ RTI ID = 0.0 > and / or < / RTI > The substance includes alcohol, amphetamine and analogous sympathetic stimulants, caffeine, cannabis, cocaine, hallucinogens, inhalants, nicotine, opioids, phencyclidine (PCP) or similar arylcyclohexylamine, and sedatives, hypnotics or anxiolytics . Also included are polysubstance dependencies and other non-known substance-related disorders. Skilled artisans will recognize that there are alternative nomenclature, disease taxonomy, and classification systems for nervous and psychotic disorders, and particularly substance-related disorders, and that these systems evolve with medical development. Accordingly, the term "substance-related disorder" is intended to include similar disorders described in other diagnostic data.

In treating, preventing, inhibiting, alleviating, or reducing the risk of a condition requiring inhibition of PDE10A, an appropriate dosage level will generally be from about 0.01 to 500 mg per kg of patient body weight per day, . Preferably, the dosage level is about 0.1 to about 250 mg / kg / day; More preferably from about 0.5 to about 100 mg / kg / day. Suitable dosage levels may be about 0.01 to 250 mg / kg / day, about 0.05 to 100 mg / kg / day, or about 0.1 to 50 mg / kg / day. Within this range, the dosage may be 0.05 to 0.5, 0.5 to 5, or 5 to 50 mg / kg / day. In the case of oral administration, the composition will preferably contain from 1.0 to 1000 mg of active ingredient, especially 1.0, 5.0, 10.0, 15.0, 20.0, 25.0, 50.0, 75.0, 100.0, 150.0, 200.0, 250.0, 300.0, 400.0, 500.0, 600.0, 750.0, 800.0, 900.0 and 1000.0 mg of the active ingredient. The compound may be administered once to four times a day, preferably once or twice a day. When the compounds of the present invention exhibit the therapeutic, prophylactic, preventive, inhibiting, reducing or reducing the risk of neurological and psychiatric disorders or other diseases, the compounds of the present invention may be administered at a daily dose of about 0.1 mg to about 100 mg per kg body weight of the animal , Preferably satisfactory results are obtained when administered in a single daily dose or in separate doses two to six times per day or in a sustained manner. For most large mammals, the total daily dose is from about 1.0 mg to about 1000 mg, preferably from about 1 mg to about 50 mg, for a 70 kg adult, and the total daily dose is generally from about 7 mg to about 350 mg daily will be. Such dosage regimens may be adjusted to provide an optimal therapeutic response. However, the specific dose level and frequency of administration for any particular patient may vary and will depend upon a variety of factors including the activity of the particular compound employed, the metabolic stability and duration of action of the compound, age, weight, general health status, sex, , Excretion rate, drug combination, severity of the particular condition, and host undergoing therapy.

The compounds of the present invention may be administered orally or parenterally, including parenteral (e.g., intramuscularly, intraperitoneally, intravenously, ICV, intracisternal injection or infusion, subcutaneous injection or implant), oral, A conventional route of administration, or a topical route of administration.

The compounds according to the present invention are further useful in methods for preventing, treating, inhibiting, alleviating or reducing the risk of the above-mentioned diseases, disorders and conditions in combination with other agents.

The compounds of the present invention may be used in combination with one or more other medicaments in the treatment, prevention, suppression, amelioration or reduction of the risk of a disease or condition for which a compound of formula I or other drug may have an effect, Combined use is safer or more efficient than drug alone. Thus, such other drug (s) may be administered concurrently or sequentially with a compound of formula (I) in an amount customarily used by the route routinely used. Where the compound of formula (I) is used contemporaneously with one or more other drugs, unit dose type pharmaceutical compositions containing such other drugs and compounds of formula (I) are preferred. However, the combination therapy may also include a therapy wherein the compound of formula I and one or more other drugs are administered in different overlap schedules. In addition, when used in combination with one or more other active ingredients, it is contemplated that the compounds of the present invention and other active ingredients may each be used at lower doses than when used alone. Accordingly, the pharmaceutical compositions of the present invention include those that contain one or more other active ingredients in addition to the compound of formula (I). The conjugate comprises a combination of a compound of the present invention with one or more other active compounds as well as one other active compound.

Likewise, the compounds of the present invention may be used in combination with other medicaments used for the prevention, treatment, inhibition, alleviation or reduction of the risk of diseases or conditions for which the compounds of the present invention are useful. These other drugs may be administered concomitantly or sequentially with the compounds of the present invention in the amounts conventionally used accordingly by routinely used routes accordingly. When the compounds of the present invention are used in combination with one or more other drugs, pharmaceutical compositions containing such other drugs in addition to the compounds of the present invention are preferred. Thus, the pharmaceutical compositions of the present invention include those that also contain one or more other active ingredients in addition to the compounds of the present invention.

The weight ratio of the compound of the present invention to the second active ingredient may vary and will depend on the effective amount of each ingredient. Generally, each effective dose will be used. Thus, for example, when the compound of the present invention is used in combination with another agent, the weight ratio of the compound of the present invention to the other agent is generally about 1000: 1 to about 1: 1000, preferably about 200: 1 Will be in the range of about 1: 200. Combinations of the compounds of the present invention and other active ingredients will generally also be within the above-mentioned ranges, but in each case an effective amount of each active ingredient should be used. In such a combination, the compound of the present invention and other active agents can be administered separately or together. In addition, administration of one component may be prior to, concurrent with, or after administration of the other agent (s).

Another aspect of the present invention relates to the use of the compounds and compositions of the present invention as diagnostic tools, particularly compounds of formula I, IA, IB, IA.a, IB.a, IA.a 'and IB.a'. Compounds of the present invention having positron-emitting isotope labels, particularly ¹¹ C or ¹⁸ F or another positron-emitting isotope, are suitable diagnostic tools for positron emission tomography (PET). Gamma-emitting isotope labels, especially compounds of the invention with ¹²³ I, are suitable diagnostic tools for single photon emission computed tomography (sPECT).

The ability of PET and sPECT to probe receptor occupancy in humans and animals by endogenous ligands or drugs has been widely recognized. It uses PET and sPECT as biomarkers for evaluating the efficacy of pharmacological intervention with drugs. The topic and use of positron emitting ligands, i. E. Compounds with positron emission isotope labels, for this purpose can be found, for example, in Burns et al. in "PET ligands for assessing receptor occupancy in vivo ", Annual Reports in Medicinal Chemistry 36 (2001), pp 267-276; Burns et al. "Positron emission tomography neuroreceptor imaging as a tool for drug discovery, research and development" Current Opinion in Chemical Biology 3 (4) (1999) 388-394; J. Hietalla, " Ligand-receptor interactions as studied by PET: implications for drug development ", Annals of Medicine (Helsinki) 31 (6) (1999), pp 438-443.

Positron suitable for isotopic labeling is in particular the radicals R ^a and radicals R ³ in the compounds of the formula I, in particular of the formulas IA, IB, IA.a, IB.a, IA.a 'and IB.a'. Suitable labels for PET include ¹¹ C or ¹⁸ F or other positron-emitting isotopes. Suitable labels for sPECT include ¹²³ I. ¹¹ C may be present, for example, in the form of an ¹¹ C-labeled alkyl group, especially as ¹¹ C-labeled methyl. ¹⁸ F label is, for example, ¹⁸ F-labeled fluoro-C ₁ -C ₄ -alkyl, for example in the form of CH ₂ CH ₂ - ¹⁸ F or as ¹⁸ F bound to an aromatic carbon, For example, as a radical R ³ bonded to Ar. ¹²³ I can be present, for example, as a label attached to an aromatic carbon, for example as a radical R ³ bonded to Ar.

Positron-emitting labeled, particularly ¹¹ C or ¹⁸ F, or other positron-emitting isotopes of compounds formula I of the present invention including the element, especially formula IA, IB, IA.a, IB.a, IA.a 'and The compounds of IB.a ' are suitable ligand tools for PET, in particular PDE10A ligand tools for the PET of the brain, especially the human brain PET. Gamma-emitting isotope labels, particularly compounds of formula I of the present invention, especially compounds of formulas IA, IB, IA.a, IB.a, IA.a 'and IB.a', with ¹²³ I are suitable ligands for sPECT Tools, especially the sPECT of the brain, specifically PDE10A ligand tools for human brain sPECT.

Particularly useful compounds of the invention by alkylation of a labeled is in the last stage of the synthesis, for example, ¹¹ C-labeled alkylating agent, in particular that can be inserted into a ¹¹ CH ₃ group, such as a ¹¹ CH ₃ I reagent , Or by insertion of an ¹⁸ F tag, for example, by nucleophilic substitution with a ¹⁸ F fluoride anion. In this regard, the general formula IA, IB, IA.a, IB.a, IA.a 'and IB.a' of the isotope-labeled precursor by the alkylation reaction of (wherein, R ^a is hydrogen), ^a radical R Compounds of formulas IA, IB, IA.a, IB.a, IA.a 'and IB.a' are particularly useful because they can be easily inserted. A compound of formula I having a carbon-bonded leaving group such as bromine, iodine, C ₁ -C ₄ -alkylsulfonyloxy or fluoro-C ₁ -C ₄ -alkylsulfonyloxy is reacted with ¹⁸ It would also be possible to introduce the ¹⁸ F fluorine label by reacting with a fluoride anion. For example, the compounds of formula IA, IB, IA.a, IB.a, IA.a 'or IB.a' (wherein, R is ^a radical C ₁ -C ₄ - alkyl and -OR ^11, R ¹¹ is C ₁ -C ₄ -alkylsulfonyl, for example, R ^a is CH ₂ CH ₂ O-SO ₂ CH ₃ ) with a ¹⁸ F fluoride anion under the conditions of a nucleophilic substitution reaction to produce ^a compound wherein R ^a is CH ₂ CH ₂ - in a ^fluoro-18 F label, such as ¹⁸ F -C ₁ -C ₄ - alkyl can be obtained. For example, it is likewise possible to introduce ¹⁸ F or ¹¹ C-label as a substituent on the aromatic carbon atom at the position of R ³ .

Other useful compounds of the present invention are those wherein the isotopic label is present in the last stage of the synthesis, for example in the presence of an acid and hydrogen peroxide, for example at the position of R < ^{3 &} gt ;, a tri (lower alkyl) ¹²³ I by substitution of the group, or ^[18 F] to a compound by the substitution of the ¹⁸ F-nitro or trimethylammonium group bonded in the presence of KF and Cryptococcus -2,2,2 fix to the aromatic carbon atom, such as R ³ group Can be inserted.

The present invention also relates to a pharmaceutical composition (i. E. Pharmaceutical) comprising at least one compound of the invention and optionally at least one suitable excipient.

These excipients / drug carriers are selected according to the pharmaceutical form and the mode of administration desired.

The compounds of the present invention may be administered orally or parenterally (e.g., intramuscularly, intraperitoneally, intravenously, ICV, intracisternal injection or infusion, subcutaneous injection or transplant), orally, sublingually, intramuscularly, intranasally, topically, transdermally, May be used to prepare pharmaceutical compositions for rectal administration and may be administered to animals or humans in unit dose form mixed with conventional pharmaceutical carriers for the prevention or treatment of the disorders or diseases.

In pharmaceutical compositions, at least one compound of the invention, alone or in combination with additional active compounds, is formulated into a suitable unit dosage form containing conventional non-toxic and / or pharmaceutically acceptable excipients . The carrier or excipient may be a solid, semi-solid or liquid substance which functions as a medium for the vehicle, carrier or active compound. Suitable excipients are listed in the specialized medical literature. The formulations may also contain pharmaceutically acceptable carriers or conventional auxiliary substances, for example, lubricants; Wetting agents; Emulsifying agents and suspending agents; Preservatives; Antioxidants; Antiirritants; Chelating agents; Coating aids; Emulsion stabilizers; Film formers; Gel formers; Odor masking agents; Taste correcting agent; Suzy; Hydrocolloid; menstruum; Solubilizing agents; corrector; Diffusion promoters; Pigments; Quaternary ammonium compounds; A refatting agent and an overfatting agent; Raw materials for ointments, creams or oils; Silicon derivatives; Diffusion aids; Stabilizers; disinfectant; Suppository base; Tableting adjuvants such as binders, fillers, lubricants, disintegrants or coatings; Propellants; drier; Emulsifier; Thickener; Wax; A plasticizer and a white mineral oil. Formulations related to this are described, for example, in Fiedler, HP, Lexikon der Hilfsstoffe fur Pharmazie, Kosmetik und angrenzende Gebiete [Encyclopedia of cosmetic and related fields], 4 ^th edition, Aulendorf: ECV-Editio -Kantor-Verlag, 1996].

Suitable unit dosage forms may be in the form of tablets, gelatin capsules, powders, granules and oral dosage forms such as solutions or suspensions for oral ingestion, sublingual, buccal, intramuscular or intranasal administration forms, aerosols, implants, subcutaneous, intramuscular or intravenous Intramuscular administration forms and rectal administration forms.

The compounds of the present invention may be used in creams, ointments or lotions for topical administration.

When the solid composition is prepared in a tablet form, the main ingredient is mixed with a pharmaceutical carrier, for example, gelatin, starch, lactose, magnesium stearate, talc, silicon dioxide and the like.

The tablets may be coated with sucrose, a cellulose derivative or another suitable material, or otherwise processed to exhibit extended or delayed activity and to release a predetermined amount of the active principle component continuously.

Formulations in the form of gelatin capsules are obtained by mixing the active ingredient with an extender and filling the resulting mixture into a soft or hard gelatin capsule.

Formulations for administration in the form of syrups or elixirs or drops may include the active ingredient, preferably with calorie-free sweeteners, methylparaben or propylparaben as preservatives, flavoring agents and suitable coloring agents.

The water-dispersible powders or granules may comprise the active ingredient in admixture with a dispersant, wetting or suspending agent, for example, polyvinylpyrrolidone and a sweetening or taste modifying agent.

Rectal administration is accomplished by the use of suppositories made using a binder that melts at rectal temperature, for example, coco butter or polyethylene glycol. Parenteral administration is carried out using an aqueous suspension comprising a pharmacologically compatible dispersant and / or wetting agent, for example, propylene glycol or polyethylene glycol, an isotonic saline solution or a sterile and injectable solution.

The active principle component may also be formulated as microcapsules or liposomes / centrosome, where appropriate, with one or more carriers or additives.

In addition to the compounds of formula I, the prodrugs thereof, the N-oxides thereof, the tautomers thereof, the hydrates thereof or the pharmaceutically acceptable salts thereof, the compositions of the present invention may further comprise additional Active ingredient < / RTI >

Thus, the present invention further relates to pharmaceutical compositions wherein a plurality of active principle components are present together and at least one of them is a compound of the present invention.

When preparing pharmaceutical compositions, the compounds according to the invention are optionally mixed or diluted with one or more carriers.

The following examples are intended to further illustrate the present invention.

Example

Abbreviation:

MeOH Methanol

DCM dichloromethane

DMF dimethylformamide

DMSO dimethylsulfoxide

THF tetrahydrofuran

TFA Trifluoroacetic acid

EtAc ethyl acetate

NBS 1-Bromopyrrolidine-2,5-dione

hr hour

HPLC High Performance Liquid Chromatography

MS (ESI) mass spectrometry (electrospray ionization)

LC / MS Coupled Liquid Chromatography-Mass Spectrometry

Prep-HPLC Preparative HPLC

RT residence time

Nuclear magnetic resonance spectrum (NMR) shows the chemical shift (delta) expressed in parts per million (ppm). The relative area of the shift in the ¹ H-NMR spectrum corresponds to the number of hydrogen atoms for a particular type of functional group in the molecule. The characteristics of the movement for the multiplicity are one line (s), wide area line (s) br., Double line (d), wide double line (d br.), Triple line (t) ), Quadruple line (q), octagonal line (quint.) And multiplet line (m). The coupling constant is in hertz (Hz).

Mass spectra were recorded using electrospray ionization.

In general, LC-MS was recorded on an Agilent 1200 HPLC / 6110 SQ system. All mass spectra were taken under the Electrospray Ionization (ESI) method.

Reversed phase HPLC (TFA method)

Samples were purified by preparative HPLC on a Phenomenex Luna C8 (2) 5 um 100 AXIA column (30 mm x 150 mm). The gradient of acetonitrile (A) and 0.1% trifluoroacetic acid (B) in water was adjusted to 50 mL / min (0-0.5 min 5% A, 0.5-8.5 min linear gradient 5-100% A, 8.7-10.7 min 100% A, 10.7-11.0 min linear gradient 100-5% A). Samples were injected in 1.5 mL DMSO: MeOH (1: 1). An Agilent 1100 Series purification system consisting of the following modules was used: an Agilent 1100 Series LC / MSD SL mass spectrometer with an API-electrospray source; Two Agilent 1100 Series dosing pumps; Agilent 1100 Series isothermal pump; An Agilent 1100 Series diode array detector with a preparative (0.3 mm) flow cell; Agilent Active-Splitter, IFC-PAL Fraction Collector / Autosampler. The constituent pump for mass spectrometry was using water with 3: 1 methanol: 0.1% formic acid at a flow rate of 1 mL / min. Fraction collection was automatically initiated when the extracted ion chromatogram (EIC) for the target mass exceeded the threshold specified in the method. The system was calibrated using the Agilent Chemstation (Rev B.10.03), Agilent A2Prep, and Leap FractPal software and custom Chemstation macros for data export.

LC-MS (Method A) was performed by applying the following conditions:

Method Info: mobile phase: A: water (0.05% TFA) B: ACN (0.05% TFA)

Gradient: 5% B for 0.1 min, 95% B for 0.7 min, 95% B for 0.9 min and 5% B within 0.01 min again.

Flow rate: 3.0 mL / min

Column: Zorbax SB-C18 Rapid Resolution HT, 4.6 mm * 30 mm, 1.8 탆

Column temperature: 45 ° C

LC-MS (Method B) was performed by applying the following conditions:

Mobile phase: A: water _{(10mM NH 4 HCO 3) B} : acetonitrile

Gradient: 5% B for 0.2 min, 95% B within 1.2 min, 95% B for 1.35 min, and 5% B within 0.01 min again.

Flow rate: 2 mL / min

Column: XBridge C18, 4.6 mm * 50 mm, 3.5 m

Column temperature: 50 ° C

I. Manufacturing Example

Precursor 1: 4- (3- (4-bromophenyl) -1-methyl-1H-pyrazol-4-yl)

One) (1- (4-bromophenyl) -2- (pyridin-4-yl) ethanone

4-Methylpyridine (10.9 g, 117 mmol) was dissolved in THF (150 ml) and cooled to -78 C with stirring. Butyl lithium (40 ml, 100 mmol) was slowly added to the solution. The resulting solution was stirred at -78 &lt; 0 &gt; C for 30 minutes. A solution of 4-bromobenzonitrile (21.84 g, 120 mmol) in THF (150 ml) was slowly added and the reaction mixture was stirred at -78 <0> C for 2 h. The resulting solution was allowed to warm and it was stirred at 22 &lt; 0 &gt; C for 18 hours. Water was added and then acidified with 48% hydrobromic acid. The solvent was removed on a rotary evaporator and the resulting acidic aqueous solution was refluxed for 2 hours. The cooled aqueous solution was extracted with diethyl ether several times, and the acidic aqueous layer was neutralized. 4-phenacylpyridine was precipitated as a yellow solid (1- (4-bromophenyl) -2- (pyridin-4-yl) ethanone (20 g, 72.4 mmol, 72.4% yield).

LC-MS (Method B): m / z 278 (M + H), RT: 1.86 min.

2) (E) -1- (4-bromophenyl) -3- (dimethylamino) -2- (pyridin-

A solution of l- (4-bromophenyl) -2- (pyridin-4-yl) ethanone (500 mg, 1.811 mmol) and 1,1- dimethoxy-N, N- dimethylmethanamine (1 g, 8.39 mmol) was heated to 100 &lt; 0 &gt; C for about 6 hours. The solvent was removed under reduced pressure to give (E) -1- (4-bromophenyl) -3- (dimethylamino) -2- (pyridin- mmol, 85% yield) as a red oil which was used in the next step without further purification.

LC-MS (Method B): m / z 331 (M + H), RT: 1.37 min.

3) 4- (3- (4-bromophenyl) -1-methyl-1H-pyrazol-4-yl)

(16.59 g, 144 mmol) and (E) -1- (4-bromophenyl) -3- (dimethylamino) -2- (pyridin- -1-one (23.85 g, 72 mmol) was stirred at about 90 &lt; 0 &gt; C for about 5 hours. The solvent was concentrated to dryness. The crude material was purified by silica gel column eluting with 2% MeOH / DCM to give 4- (3- (4-bromophenyl) -1-methyl-1H-pyrazol-4-yl) pyridine (9.6 g, 30.6 mmol, 42.4% yield).

LC-MS (Method B): m / z 314 (M + H), RT: 1.46 min.

Precursor 2: 2- [2- [4- (4-Bromo-1-methyl-pyrazol-3- yl) phenyl] ethynyl] -6- methylpyridine

(One) 3- (4-Bromophenyl) -lH-pyrazole

5 g (25.0 mmol) of 4-bromoacetophenone and 3.59 g (30.1 mmol) of 1,1-dimethoxy-N, N-dimethylmethanamine were added to 40 ml of DMF. The mixture was heated to 80 &lt; 0 &gt; C overnight. After cooling, the mixture was poured into water (150 mL) and extracted with EA (100 mL x 3). The combined organic phases were washed with brine and concentrated to give a red liquid (6 g). The product thus obtained was redissolved in 50 ml of ethanol and treated with hydrazine monohydrate (3.5 ml, 75 mmol). The reaction was stirred at 80 &lt; 0 &gt; C for 2 h, then cooled to 23 &lt; 0 &gt; C and poured into ice water. A solid precipitated out of the solution, which was filtered, washed with water and dried to give 3.6 g of 3- (4-bromophenyl) -1H-pyrazole as a yellow solid (yield: 80%).

(2) 3- (4-bromophenyl) -1-methylpyrazole and 5- (4-bromophenyl) -1-methylpyrazole

Sodium hydride (0.43g, 17.9mmol) was added slowly to a solution of 3- (4-bromophenyl) -1H- pyrazole (1.0g, 4.48mmol) in 50ml THF under N _2. The mixture was stirred for 1 hour and then iodomethane (1.27 g, 8.97 mmol) was added to the suspension. The mixture was stirred at 23 &lt; 0 &gt; C for 2 hours. Water (20 ml) was added and extracted with EtAc (50 mL x 3). The combined organic phases were washed with brine, dried, concentrated and purified by column chromatography to give 1.0 g of colorless liquid (mixture) (yield: 90%).

LC-MS (method B): m / z 237 (M + H) <+> RT = 1.62 min / 2.5 min

(3) Trimethyl- [2- (6-methyl-2-pyridyl) ethynyl] silane

Trimethylsilane (1.88g, 19.2mmol) ethynyl] To a solution of Et ₃ N 2- bromo-6-methylpyridine (3g, 17.44mmol) in 50mL of degassed, copper iodide (I) (0.33g, 1.74mmol) And bis (triphenylphosphine) palladium (II) chloride (1.22 g, 1.74 mmol) were added. The resulting solution was stirred under N ₂ overnight at room temperature. The black solution was then added with 30 mL of H ₂ O and extracted with EtAc (50 mL × 3). The combined organic phases were washed with brine, dried, concentrated and purified by silica gel column to give 2.5 g of trimethyl- [2- (6-methyl-2-pyridyl) ethynyl] silane as a brown liquid (yield: 74% Lt; / RTI &gt;

(4) Ethynyl] -6-methylpyridine and 2- [2- [4- (1-methyl-pyrazol-3- yl) ) Phenyl] ethynyl] -6-methylpyridine

To a solution of 3- (4-bromophenyl) -1-methylpyrazole obtained in Step 2 and 5- (4-bromophenyl) -1-methylpyrazole (3.0 g, 15.9 mmol) (3.76 g, 15.8 mmol) and triethylamine (6.41 g, 63.4 mmol), copper iodide (I) (0.30 g, 1.6 mmol) and bis (triphenylphosphine Pin) palladium (II) chloride (1.11 g, 1.60 mmol) was added sequentially to 30 mL of DMF. The reaction was heated to 60 &lt; 0 &gt; C and a solution of tetra-n-butylammonium fluoride (4.6 g, 17.4 mmol) in THF was slowly added to the suspension. To the mixture was added water, filtered and extracted with EtAc (100 mL x 3). The combined organic phases were washed with brine, dried, concentrated and purified on silica gel column to give 2- [2- [4- (1-methyl-pyrazol-3- yl) phenyl] ethynyl] -6- methylpyridine And 1.4 g (yield: 32%) of a mixture of 2- [2- [4- (1-methyl-pyrazol-5-yl) phenyl] ethynyl] -6-methylpyridine.

LC-MS (method B): m / z 274 (M + H) RT = 1.71 min / 2.5 min

(5) Yl] phenyl] ethynyl] -6-methylpyridine and 2- [2- [4- (4-bromo- Methyl-pyrazol-5-yl) phenyl] ethynyl] -6-methylpyridine

NBS (3.94 g, 22.1 mmol) was added to a solution of the mixture obtained in step 4 (5.5 g, 20.1 mmol) in 50 mL of anhydrous DMF. The mixture was stirred at 23 ℃ for 30 minutes and then poured into H ₂ O 100ml. The resulting white precipitate was extracted with EtAc (150 ml x 3). The combined organic phases were washed with brine, dried, concentrated and purified by Prep-HPLC to afford 2- [2- [4- (4-bromo-1-methyl-pyrazol- ] -6-methylpyridine and 2.5 g of 2- [2- [4- (4-bromo-1-methyl-pyrazol-5-yl) phenyl] ethynyl] %).

2- [2- [4- (4-Bromo-1-methyl-pyrazol-3- yl) phenyl] ethynyl] -6- methylpyridine

Method of Prep-HPLC:

Main solvent MeOH (containing 0.1% DEA)

Column OJ-H 4.6 mm * 250 mm 5 탆

                 (Daicel Chemical Industries Co. Ltd)

Sample well P1: 2C

Column temperature 40 ° C

CO ₂ flow rate 2.25

Common flow rate 0.75

Solvent% 25

Total flow 3

Anterior pressure 196

Rear pressure 150

Pressure drop 46

PDA starting wavelength 214 nm

PDA stop wavelength 359 nm

Precursor 3: 2- [2- [4- (4-Bromo-1-methyl-pyrazol-5-yl) phenyl] ethynyl] -6- methylpyridine

The compound was prepared as described for Precursor 2 and isolated from the crude reaction product.

Precursor 4: 3-Bromo-2- (4-pyridyl) -6,7-dihydro-5H-pyrrolo [

One) Pyrrolidin-2-imine hydrochloride

In a 250 mL bottom flask, ammonia was bubbled through to ethanol (80 mL) cooled to-78 C for 45 min. The saturated solution thus obtained was transferred to a Parautoclave containing 4-chlorobutanenitrile (60 g, 580 mmol) and the mixture was stirred and heated to 120 ° C for 16 hours. The reaction mixture was cooled and transferred to a round bottom flask and the solvent was removed under reduced pressure to give a yellow solid which was washed with diethyl ether and dried under high vacuum to yield an off-white solid (19.5 g, 232 mmol, 40% yield) Respectively.

2) 6-dihydro-5H-pyrrolo [1,2-a] imidazole

DMF (65ml) solution of 2-bromo-1- (pyridin-4-yl) ethanone (12.8g, 64mmol), pyrrolidine-2-imine hydrochloride (10.8g, 89.4mmol) and Na ₂ CO ₃ ( 33.8 g, 319 mmol) was stirred in a 250 mL three-necked flask for 16 h and heated to 80 &lt; 0 &gt; C. The mixture was cooled to 22 &lt; 0 &gt; C and poured into water (500 ml). The product was partitioned between ethyl acetate (300 ml) and the aqueous phase. The aqueous phase was extracted three times with ethyl acetate (300 mL each). The combined organic phases were washed with water and then washed with brine and dried over anhydrous Na ₂ SO _4. After filtration, the filtrate was concentrated to give 2- (pyridin-4-yl) -6,7-dihydro-5H-pyrrolo [1,2- a] imidazole (7.03 g, 38 mmol, Respectively.

3) (3-bromo-2- (pyridin-4-yl) -6,7-dihydro-5H-pyrrolo [

NBS (890 mg, 5 mmol) was added to a solution of 2- (pyridin-4-yl) -6,7-dihydro-5H-pyrrolo [1,2-a] imidazole (740 mg, 4 mmol) in small portions. After complete addition, the mixture was stirred at 22 &lt; 0 &gt; C for 2 hours. The reaction mixture was poured on ice-water, it was in the 22 ℃ stirred for 15 minutes and then was added a 10% aqueous solution of Na ₂ S ₂ O _3. The resulting solution was stirred for 1 hour and then extracted with ethyl acetate. The combined organic phases were washed with water and then washed with brine, dried over anhydrous Na ₂ SO _4. After evaporation under reduced pressure, crude product was obtained which was purified via a chromatographic column (MeOH / DCM = 1/10) to give a light yellow solid, 3-bromo-2- (pyridin- - dihydro-5H-pyrrolo [1,2-a] imidazole (924 mg, 3.5 mmol, 87% yield).

LCMS (ESI +): m / z 266 (M + H) &lt; ⁺ & gt ^; , RT: 1.64 min. (Method A)

Example 1:

4- (1-methyl-3- (4 - ((1-methyl -1 H-imidazol-ethynyl-5-yl)) phenyl) -1 H-pyrazol-4-yl) pyridine

In a 4 mL vial, 2-dicyclohexylphosphino-2 ', 6'-diisopropoxybiphenyl (28 mg, 0.06 mmol) was added followed by palladium (II) acetate (5.5 mg, 0.02 mmol) and pure triethylamine (51 [mu] L, 0.37 mmol). To this was added 4- (3- (4-bromophenyl) -1-methyl-1H-pyrazol-4-yl) pyridine (38 mg, 0.12 mmol) dissolved in a 10% Ethyl-1-methyl-1H-imidazole (358 mg, 0.36) dissolved in 10% water / THF solution (0.9 mL) was then added. It was capped with a diaphragm cap, vacuum treated and purged with nitrogen 3 to 4 times. This was allowed to stir at 80 C for 5 hours. 5-hour equivalent amounts of 2-dicyclohexylphosphino-2 ', 6'-diisopropoxybiphenyl, palladium (II) acetate, triethylamine and 5-ethynyl- Reprocessed, refereed with nitrogen and allowed to stir at 80 degrees Celsius for 16 hours. Upon completion, the product was passed through a Celite cartridge. The reaction was checked by LC / MS and dried. The residue was dissolved in 1: 1 DMSO / MeOH. Purification by reverse phase HPLC (TFA method) provided the title compound (8.9 mg, 13%). The product was identified by ¹ H NMR, MS and LC / MS.

The compounds of Examples 2 to 11 and 13 to 23 were prepared in analogy to the procedure described in Example 1.

Example 2:

2 - ((4- (1 -methyl-4- (pyridin-4-yl) -1 H- pyrazol-3- yl) phenyl) ethynyl)

Example 3:

5-methyl-2 - ((4- (1-methyl-4- (pyridin-4-yl) -1 H-pyrazol-3-yl) phenylethynyl)) pyridine

Example 4:

4- (1-methyl-3- (4 - ((1-propyl -1 H-pyrazol-4-yl) ethynyl) phenyl) -1 H-pyrazol-4-yl) pyridine

Example 5:

5-fluoro-2 - ((4- (1-methyl-4- (pyridin-4-yl) -1 H-pyrazol-3-yl) phenylethynyl)) pyridine

Example 6:

3-methyl-2 - ((4- (1-methyl-4- (pyridin-4-yl) -1 H-pyrazol-3-yl) phenylethynyl)) pyridine

Example 7:

4- (1-methyl-3- (4 - ((1-methyl -1 H-imidazol-ethynyl-2-yl)) phenyl) -1 H-pyrazol-4-yl) pyridine

Example 8:

4-methyl-2 - ((4- (1-methyl-4- (pyridin-4-yl) -1 H-pyrazol-3-yl) phenylethynyl)) pyridine

Example 9:

2-methyl-6 - ((4- (1-methyl-4- (pyridin-4-yl) -1 H-pyrazol-3-yl) phenylethynyl)) pyridine

Example 10:

4- (1-methyl-3- (4 - ((1-methyl-1 H -1-ethynyl-4-yl)) phenyl) -1 H-pyrazol-4-yl) pyridine

Example 11:

4- (3- (4 - (( 1 H - pyrazol-4-yl) ethynyl) phenyl) -1-methyl -1 H - pyrazol-4-yl) pyridine

Example 12:

2 - ((4- (1 -methyl-4- (pyridin-4-yl) -1H-pyrazol-3- yl) phenyl) ethynyl) quinoline

Pyridine (200 mg, 0.637 mmol) was added to a solution of tetrakis (triphenylphosphine) palladium (0) in DMF (1 ml) ) (36.8 mg, 0.032 mmol) and copper (I) iodide (6.06 mg, 0.032 mmol). 2-ethynylquinoline (134 mg, 0.700 mmol) in DMF (3 ml) was added followed by triethylamine (0.106 ml, 0.764 mmol). The vessel was washed with argon and then the mixture was stirred and heated in microwave (110 [deg.] C, 300 W, 2 h). Water and EtOAc were added, the organic layer was separated and the aqueous layer was extracted with EtOAc. The combined organic layers were washed with water and dried over MgSO4. Yl) phenyl) ethynyl) quinoline (70 mg, 0.25 mmol) in dichloromethane (10 mL) was purified by flash chromatography (DCM / AcCN) 29%).

ESI-MS [M + H &lt; + &gt;] = 387.1;

Example 13:

2- [2- [4- [1 -methyl-4- (4-pyridyl) pyrazol-3-yl] phenyl] ethynyl] -1,5-naphthyridine

MS (ESI) [M + Na +] = 410.20, [M + H +] = 388.20

Example 14:

3-yl] phenyl] ethynyl] imidazo [1,2-a] pyridine

MS (ESI) [M + H &lt; + &gt;] = 376.10

Example 15:

Yl] phenyl] ethynyl] - lH-pyrrolo [2,3-b] pyridine

MS (ESI) [M + H &lt; + &gt;] = 376.10

Example 16:

Methyl-2- [2- [4- [1 -methyl-4- (4-pyridyl) pyrazol-3-yl] phenyl] ethynyl] quinoline

MS (ESI) [M + H &lt; + &gt;] = 401.10

Example 17:

2- [2- [4- [1-methyl-4- (4-pyridyl) pyrazol-3-yl] phenyl] ethynyl] thiazole; 2,2,2-Trifluoroacetic acid

MS (ESI) [M + H &lt; + &gt;] = 343.10

Example 18:

2- [2- [4- [1 -Methyl-4- (4-pyridyl) pyrazol-3-yl] phenyl] ethynyl] quinoxaline; 2,2,2-Trifluoroacetic acid

MS (ESI) [M + H &lt; + &gt;] = 388.20

Example 19:

3- [2- (6-methyl-2-pyridyl) ethynyl] -2- (4-pyridyl) -6,7-dihydro-5H-pyrrolo [1,2-a] imidazole; 2,2,2-Trifluoroacetic acid

MS (ESI) [M + H &lt; + &gt;] = 301.10

Example 20:

2-methoxy-6- [2- [4- [1-methyl-4- (4-pyridyl) pyrazol-3-yl] phenyl] ethynyl] pyridine; 2,2,2-Trifluoroacetic acid

MS (ESI) [M + Na +] = 389.10, [M + H +] = 367.10

Example 21:

2- [4- [1 -methyl-4- (4-pyridyl) pyrazol-3-yl] phenyl] ethynyl]

MS (ESI) [M + H &lt; + &gt;] = 367.10

Example 22:

4- [1-methyl-3- [4- (2-phenylethynyl) phenyl] pyrazol-4-yl] pyridine; 2,2,2-Trifluoroacetic acid

MS (ESI) MS (ESI) [M + H &lt; + &gt;] = 336.90

Example 23:

Pyridyl) ethynyl] phenyl] -2- (4-pyridyl) -6,7-dihydro-5H-pyrrolo [1,2- a ] Imidazole

MS (ESI) [M + H &lt; + &gt;] = 377.90

Example 24:

3-yl] phenyl] ethynyl] pyridine &lt; / RTI &gt;

Ethynyl) -6- methylpyridine (25 mg, 0.07 mmol), 4- (4-bromo-1-methyl-1H-pyrazol- (4,4,5,5-tetramethyl-1,3,2 dioxaborolan-2-yl) -1H- pyrazole (14mg, 0.07mmol) and _{Pd (PPh 3) 4 (8.2mg} , 7 saturated NaHCO ₃ was added to the aqueous solution (1.5ml) in ㎛ol). The mixture was then stirred for 10 minutes at 150 &lt; 0 &gt; C and 300 W under microwave (CEM apparatus). The mixture was treated with aq. Poured into K ₂ CO ₃ (5%, 10 ml) and extracted with ethyl acetate (3x, 10 ml). The combined organic phases were washed with water (3x, 30ml), dried over Na ₂ SO ₄ and, filtered and evaporated in vacuo. The residual oil was purified on silica gel (preparative TLC, CH ₂ Cl ₂ : MeOH 19: 1) to give the title compound (4.4 mg, 18%).

The compounds of examples 25 to 32 were prepared analogously to example 24 using precursor 2 or 3.

Example 25:

5- [1 -Methyl-3- [4- [2- (6-methyl-2-pyridyl) ethynyl] phenyl] pyrazol-4-yl] pyrimidine

MS (ESI) [M + Na +] = 374.10, [M + H +] = 352.10

Example 26:

Methyl-6- [2- [4- [2-methyl-4- (4-pyridyl) pyrazol-3-yl] phenyl] ethynyl]

MS (ESI) [M + H &lt; + &gt;] = 351.10

Example 27:

3-yl] phenyl] ethynyl] -pyridine hydrochloride (prepared according to the procedure described for the synthesis of 2-methyl-4-

MS (ESI) [M + H &lt; + &gt;] = 354.10

Example 28:

4- [1 -methyl-3- [4- [2- (6-methyl-2-pyridyl) ethynyl] phenyl] pyrazol-4-yl] pyridazine

MS (ESI) [M + H &lt; + &gt;] = 352.10

Example 29:

2-Methyl-6- [2- [4- [1-methyl-4- (3-pyridyl) pyrazol-3-yl] phenyl] ethynyl] pyridine; 2,2,2-Trifluoroacetic acid

MS (ESI) [M + Na +] = 373.10, [M + H +] = 351.10

Example 30:

2- [2- [4- [4- (4-Fluorophenyl) -1-methyl-pyrazol-3-yl] phenyl] ethynyl] -6-methyl-pyridine; 2,2,2-Trifluoroacetic acid

MS (ESI) [M + H &lt; + &gt;] = 368.10

Example 31:

2- [2- [4- [4- (4-methoxyphenyl) -1-methyl-pyrazol-3-yl] phenyl] ethynyl] -6-methyl-pyridine; 2,2,2-Trifluoroacetic acid

MS (ESI) [M + H &lt; + &gt;] = 380.10

Example 32:

2- [2- [2-Methoxy-4- [1 -methyl-4- (4-pyridyl) pyrazol-3-yl] phenyl] ethynyl] -6-methyl-pyridine; 2,2,2-Trifluoroacetic acid

MS (ESI) [M + H &lt; + &gt;] = 381.10

II. Biological test

a) Measurement of PDE activity

Recombinant PDE proteins are used in in vitro enzyme reactions for the measurement of PDE activity. These recombinant proteins, including PDE10A (human, rat and mouse PDE10) and isoforms of PDE 1, 3, 4 and 5, were purchased from BSE Bioscience, a commercial vendor. Enzyme activity of PDE was measured by cAMP measurement kit from CisBio (IBA) using HTRF technology.

The PDE enzyme reaction was performed in assay buffer (20 mM Tris-HCl pH 7.5, 10 mM MgCl ₂ , 0.1% bovine serum albumin) containing the enzyme and the substrate. The PDE enzyme concentration ranged from 10 pM to 250 pM, depending on the specific activity of each enzyme. The substrate cyclic nucleotide (cAMP or cGMP) concentration used in the assay was 20 nM for PDE10 and 100 nM for the other PDEs. The inhibitory effect of the compounds was determined by incubating various concentrations of the inhibitor in the enzyme assay. Typically, the compounds were serially diluted in DMSO and then further diluted in assay buffer. Various concentrations of compounds were then mixed with the PDE enzyme. The reaction was initiated by the addition of cyclic nucleotide substrate and incubated at 29 DEG C for 60 minutes. The reaction was stopped by addition of lysis buffer from the assay kit. CAMP-d2 and anti-cAMP cryptate in lysis buffer detected the level of residual cAMP from the PDE hydrolysis reaction. PDE activity is inversely correlated with the amount of cAMP remaining in the reaction and can be converted to an active percentage for the unconstrained control (100%). Thus, the IC ₅₀ value of the inhibitor can be obtained by plotting the inhibitor concentration against the PDE activity at that concentration. The results are shown in Table 1.

1) +++: IC ₅₀ < 100 nM

++: 100nM ≤ IC ₅₀ ≤ 200nM

+: 200 nM < IC ₅₀ < 500 nM

b) Measurement of half-life of microcrystals:

The metabolic stability of the compounds of the present invention was determined by the following assay.

The test substance was incubated at a concentration of 0.5 [mu] M as follows:

0.5 [mu] M test material is pre-incubated with liver microsomes from different species (rats, humans or other species) in 0.05M potassium phosphate buffer at pH 7.4 for 5 minutes at 37 [deg.] C in microtiter plates Protein / ml). The reaction is initiated by the addition of NADPH (1 mg / mL). After 0, 5, 10, 15, 20 and 30 minutes, 50 [mu] l aliquots are removed, the reaction is stopped immediately and the same volume of acetonitrile is allowed to cool. The sample is frozen until analysis. The residual concentration of the undissociated test substance is measured by MSMS. The half-life (T1 / 2) is determined from the gradient of the signal / unit time plot of the test substance, and assuming a primary kinetics, it is possible to calculate the half-life of the test substance from the decrease in concentration of the compound over time. The microcrystalline clearance (mCl) is calculated from mCl = ln2 / T1 / 2 / (content of microcrystalline protein in mg / ml) × 1000 ml / min / mg (modified from Di, The Society for Biomolecular Screening, 2003, 453-462; Obach, DMD, 1999 vol 27. N 11, 1350-1359). The results are shown in Table 2.

Ex. Example

mCl Microcrystalline clearance

2) ++: <100 μl min ^-1 mg ^-1

+: 100 - 220 μl min ^-1 mg ^-1

o: > 220 [mu] l min ^-1 mg ^-1

na Not available (not available)

Claims (40)

Compounds of formula (I), and N-oxides, prodrugs, tautomers and hydrates thereof, and pharmaceutically acceptable salts thereof.
Formula I

In the above formula (I)
Y ¹ and Y ² are adjacent atoms in Het ¹ , which are independently selected from the group consisting of carbon and nitrogen;
k is 0, 1, 2 or 3;
Het ¹ is a divalent monocyclic 5 or 6 membered heteroaromatic radical having as ring members 1, 2 or 3 heteroatoms or heteroatom moieties selected from O, S, N and NR ^a , or O , A divalent fused bicyclic 8-, 9- or 10-membered heteroaromatic radical having 1, 2, 3 or 4 heteroatoms or heteroatom moieties selected from S, N and NR ^a as ring members;
Het ² is
i. O, S, S = O, S (= O) _2, N, and saturated or partially unsaturated, 5-to 10-membered having from 1, 2 or 3 heteroatoms or heteroatom moiety selected from NR ^1a as ring members Monocyclic or heterobicyclic radicals,
ii. 5 or 6 membered heteroaryl having 1, 2 or 3 heteroatoms or heteroatom moieties selected from O, S, N and NR ^1a as ring members,
iii. 9 or 10-membered heteroaryl having 1, 2 or 3 heteroatoms or heteroatom moieties selected from O, S, N and NR ^1a as ring members,
iv. Phenyl
, &Lt; / RTI &gt;
Wherein Het ² may have 1, 2 or 3 radicals R ¹ ;
Cyc
i. Monocyclic 5 or 6 membered heteroaryl having 1 or 2 nitrogen atoms and any additional heteroatoms selected from O, S and N as ring members, which are unsubstituted or substituted by 1, 2, 3 or 4 Which may have the same or different substituents R &lt; ² &gt;),
ii. A fused 8-, 9- or 10-membered bicyclic hetaryl having one heteroatom selected from O, S and N and optionally one, two or three nitrogen atoms as ring members, wherein the fused bicyclic Hetaryl is unsubstituted or may have 1, 2, 3 or 4 identical or different substituents R &lt; ² &gt;),
iii. Phenyl having monocyclic hetaryl radicals having one or two nitrogen atoms and any further heteroatoms selected from O, S and N as ring members, which may be monocyclic hetaryl, in addition to one, two or three ^Which may have the same or different substituents R &lt; ^2a &gt;) and
iv. 2 or 3 heteroatoms or heteroatom moieties selected from O, S, S = O, S (= O) ₂ , N and NR ^1a as ring members and 1, 2 or 3 identical or different substituents R ^2b C ₅ -C ₈ and may have a-cyclic cycloalkyl or saturated or partially unsaturated 5- to 10-membered heterocyclic mono or bicyclic heteroaryl radical
&Lt; / RTI &gt;
Ar is phenylene or divalent 6-membered hetaryl having 1, 2 or 3 nitrogen atoms as ring members, wherein the phenylene and the divalent 6-membered hetaryl are unsubstituted or substituted by 1, 2, 3 or 4 Have the same or different substituents R ³ ,
R is attached to a carbon atom of Het ^1, R is a ^{halogen, CN, NR 13 R 14,} C (O) NR 13 R 14, C 1 -C 6 - alkyl, C ₂ -C ₆ - alkenyl, C ₂ -C ₆ - alkynyl, trimethylsilyl, C ₁ -C ₆ - alkyl sulfanyl, C ₁ -C ₆ - alkylsulfonyl, fluorinated C ₁ -C ₆ - alkyl sulfanyl, fluorinated C ₁ -C ₆ - alkyl sulfonic C ₁ -C ₄ -alkyl-OR ¹¹ , C ₁ -C ₄ -alkyl-SR ¹² , C ₁ -C ₄ -alkyl-NR ¹³ R ¹⁴ , C ₁ -C ₆ -alkoxy, OC ₁ -C ₄ Alkyl-OR ¹¹ , OC ₁ -C ₄ -alkyl-SR ¹² , OC ₁ -C ₄ -alkyl-NR ¹³ R ¹⁴ , C ₂ -C ₆ -alkenyloxy, C ₁ -C ₆ -fluoroalkyl, Is selected from the group consisting of C ₁ -C ₆ -fluoroalkoxy, C ₃ -C ₆ -cycloalkyl and C ₃ -C ₆ -cycloalkyl-C ₁ -C ₄ -alkyl, wherein in said last two radicals Cycloalkyl moiety is unsubstituted, partially fluorinated or fully fluorinated, or is substituted with 1, 2 or 3 methyl groups;
R ^a is ^{hydrogen, C (O) NR 13 R} 14, C 1 -C 6 - alkyl, C ₂ -C ₆ - alkenyl, C ₂ -C ₆ - alkynyl, trimethylsilyl, C ₁ -C ₄ - alkyl, -OR ^11, C ₁ -C ₄ - alkyl, -SR ^12, C ₁ -C ₄ - alkyl, _{^{-NR 13 R 14, C 1 -C}} 6 - alkyl, fluoroalkyl, C ₁ -C ₆ - alkoxy, C ₃ fluoro -C ₆ - cycloalkyl, and C ₃ -C ₆ - cycloalkyl, -C ₁ -C ₄ - is selected from the group consisting of alkyl, where the last two radicals cycloalkyl moiety in is unsubstituted or substituted with a fluorinated part Or is fully fluorinated, or is substituted with 1, 2 or 3 methyl groups;
When attached to two radicals and R is or R is a radical with the radical R ^a, adjacent ring atoms, linear C ₃ -C ₅ -, and may form a alkanediyl, wherein one or two CH ₂ moiety T is C = O, O, S, S (= O), S (= O) can be replaced by a ₂ or NR ', where alkanediyl thing is optionally substituted with halogen, C ₁ -C ₄ - alkyl, C ₁ -C ₄ - fluoroalkyl, C ₁ -C ₄ - alkoxy and C ₁ -C ₄ - may have one or two radicals selected from alkoxy and fluoro;
R ¹ is attached to the carbon atom of Het ² and R ¹ is halogen, CN, NR ¹³ R ¹⁴ , C (O) NR ¹³ R ¹⁴ , C ₁ -C ₆ -alkyl, C ₂ -C ₆ -alkenyl, C ₂ -C ₆ - alkynyl, trimethylsilyl, C ₁ -C ₆ - alkyl sulfanyl, C ₁ -C ₆ - alkylsulfonyl, fluorinated C ₁ -C ₆ - alkyl sulfanyl, fluorinated C ₁ -C ₆ - alkylsulfonyl, C ₁ -C ₄ - alkyl, -OR ^11, C ₁ -C ₄ - alkyl, -SR ^12, C ₁ -C ₄ - alkyl, _{^{-NR 13 R 14, C 1 -C}} 6 - alkoxy, OC ₁ - C _{4-fluoro-alkyl} -OR ^11, OC ₁ -C ₄ - alkyl, -SR ^12, OC ₁ -C ₄ - alkyl, _{^{-NR 13 R 14, C 2 -C}} 6 - alkenyloxy, C ₁ -C ₆ Is selected from the group consisting of alkyl, C ₁ -C ₆ -fluoroalkoxy, C ₃ -C ₆ -cycloalkyl and C ₃ -C ₆ -cycloalkyl-C ₁ -C ₄ -alkyl, The cycloalkyl moiety in the radical is unsubstituted, partially fluorinated or fully fluorinated, or is substituted by 1, 2 or 3 methyl groups;
R ^1a is ^{hydrogen, C (O) NR 13 R} 14, C 1 -C 6 - alkyl, C ₂ -C ₆ - alkenyl, C ₂ -C ₆ - alkynyl, trimethylsilyl, C ₁ -C ₄ - alkyl, -OR ^11, C ₁ -C ₄ - alkyl, -SR ^12, C ₁ -C ₄ - alkyl, _{^{-NR 13 R 14, C 1 -C}} 6 - alkyl, fluoroalkyl, C ₁ -C ₆ - alkoxy, C ₃ fluoro -C ₆ - cycloalkyl, and C ₃ -C ₆ - cycloalkyl, -C ₁ -C ₄ - is selected from the group consisting of alkyl, where the last two radicals cycloalkyl moiety in is unsubstituted or substituted with a fluorinated part Or is fully fluorinated, or is substituted with 1, 2 or 3 methyl groups;
R ² is selected from the group consisting of halogen, C ₁ -C ₄ -alkyl, C ₁ -C ₄ -alkoxy, C ₁ -C ₄ -fluoroalkyl, C ₁ -C ₄ -fluoroalkoxy, C ₁ -C ₄ -alkoxy-C ₁ -C ₄ - alkoxy, C ₁ -C ₄ - alkoxy -C ₁ -C ₄ - alkyl, OH, hydroxy -C ₁ -C ₄ - alkyl, OC ₃ -C ₆ - cycloalkyl, benzyloxy, C ( _{O) O- (C 1 -C 4} - _{alkyl), O- (C 1 -C 4} - ^{_{alkyl) -CO 2 H, NR 23 R}} 24, C (O) NR 23 R 24, C 1 -C 4 - alkyl, ^{-NR 23 R 24, -NR 25 -C} (O) -NR 23 R 24, NR 25 -C (O) O- (C 1 -C 4 - _{^{alkyl), -NR 25 -SO 2 -R 22}} , Phenyl, CN, -SF ₅ , -OSF ₅ , -SO ₂ R ²² , -SR ²² , trimethylsilyl and C ₃ -C ₆ -cycloalkyl, wherein the cycloalkylmeyer in the last radical T is unsubstituted, partially fluorinated or fully fluorinated, substituted by 1, 2 or 3 methyl groups,
Two radicals R ² bonded to adjacent ring atoms may form a linear C ₃ -C ₅ -alkanediyl wherein one or two CH ₂ moieties may be replaced by C═O, O, S, S ( = O), S (= O) ₂ or NR 'where the alkanediyl is unsubstituted or substituted by halogen, C ₁ -C ₄ -alkyl, C ₁ -C ₄ -fluoroalkyl, C ₁ -C ₄ - alkoxy and C ₁ -C ₄ - may have one or two alkoxy radicals selected from fluoro;
R ^2a has one of the meanings given for R ² , or one radical R ^2a has one or two nitrogen atoms and a 5 membered ring with any further heteroatom selected from O, S and N as ring members and won or 6 may be a hat-aryl, wherein aryl is optionally substituted with het, halo, OH, C ₁ -C ₄ - alkyl, C ₁ -C ₄ - haloalkyl, C ₁ -C ₄ - alkoxy and C ₁ - C ₄ -haloalkoxy, &lt; / RTI &gt;
R ^2b is selected from the group consisting of halogen, C ₁ -C ₄ -alkyl, C ₁ -C ₄ -alkoxy, C ₁ -C ₄ -fluoroalkyl, C ₁ -C ₄ -fluoroalkoxy, C ₃ -C ₆ -cycloalkyl, C ₁ -C ₄ -alkoxy-C ₁ -C ₄ -alkoxy, C ₁ -C ₄ -alkoxy-C ₁ -C ₄ -alkyl, OH, hydroxy-C ₁ -C ₄ -alkyl, OC ₃ -C ₆ (C ₁ -C ₄ -alkyl), O- (C ₁ -C ₄ -alkyl) -CO ₂ H, NR ²³ R ²⁴ , C (O) NR ²³ R ^24, C ₁ -C ₄ - alkyl, ^{-NR 23 R 24, -NR 25 -C} (O) -NR 23 R 24, NR 25 -C (O) O- (C 1 -C 4 - alkyl), - NR ²⁵ -SO ₂ -R ²² , phenyl, CN, -SF ₅ , -OSF ₅ , -SO ₂ R ²² , -SR ²² and trimethylsilyl,
The two radicals R &lt; ^2a &gt; bonded to the adjacent ring atoms are fused benzene having one ring member selected from the group consisting of O, S, N or NR 'and optionally one or two further N-atoms as ring members may form a ring or a fused 5-or 6-membered heteroaromatic ring, wherein said fused benzene or heteroaromatic ring is optionally substituted with, halogen, OH, C ₁ -C ₄ - alkyl, C ₁ -C ₄ - Two, three or four radicals selected from fluoroalkyl, C ₁ -C ₄ -alkoxy and C ₁ -C ₄ -fluoroalkoxy;
R ³ is independently from each other selected from the group consisting of halogen, CN, NR ³³ R ³⁴ , C (O) NR ³³ R ³⁴ , C ₁ -C ₆ -alkyl, C ₂ -C ₆ -alkenyl, C ₂ -C ₆ -alkynyl trimethylsilyl, C ₁ -C ₆ - alkyl sulfanyl, C ₁ -C ₆ - alkylsulfonyl, fluorinated C ₁ -C ₆ - alkyl sulfanyl, fluorinated C ₁ -C ₆ - alkylsulfonyl, C ₁ -C _4-alkyl, -OR ^31, C ₁ -C ₄ - alkyl, -SR ^32, C ₁ -C ₄ - alkyl, _{^{-NR 33 R 34, C 1 -C}} 6 - alkoxy, OC ₁ -C ₄ - alkyl, -OR ^31, OC ₁ -C ₄ - alkyl, -SR ^32, OC ₁ -C ₄ - alkyl, _{^{-NR 33 R 34, C 2 -C}} 6 - alkenyloxy, C ₁ -C ₆ - alkyl, fluoroalkyl, C ₁ -C ₆ - C ₃ -C ₆ -cycloalkyl and C ₃ -C ₆ -cycloalkyl-C ₁ -C ₄ -alkyl, wherein the cycloalkyl moiety in the last two radicals is selected from the group consisting of Unsubstituted, partially fluorinated or fully fluorinated, or substituted with 1, 2 or 3 methyl groups;
R ^11, R ¹² are independently hydrogen, C ₁ -C ₄ together -alkyl, C ₁ -C ₄ - fluoroalkyl, C ₃ -C ₆ - cycloalkyl, and C ₃ -C ₆ - cycloalkyl, -C ₁ - C ₄ - is selected from the group consisting of alkyl, wherein, R ¹¹ is also C ₁ -C ₄ - alkylsulfonyl and C ₁ -C ₄ - alkylsulfonyl may imidazol fluoro;
R ^13, R ¹⁴ are independently hydrogen, C ₁ -C ₄ together -alkyl, C ₁ -C ₄ - fluoroalkyl, C ₃ -C ₆ - cycloalkyl, and C ₃ -C ₆ - cycloalkyl, -C ₁ - C ₄ -alkyl;
R ¹³ and R ¹⁴ together with the N atom to which they are attached form one, two or three further identical or different heteroatoms or heteroatom-containing groups selected from the group of O, N, S, SO and SO ₂ , 3-membered to 7-membered nitrogen heterocycle which may have 1, 2, 3, 4, 5 or 6 substituents which may be identical or different and are selected from C ₁ -C ₄ -alkyl and fluorine;
R ²¹ , R ²² , R ³¹ and R ³² have one of the meanings given for R ¹¹ , R ¹² ;
R ²³ , R ²⁴ , R ³³ and R ³⁴ have one of the meanings given for R ¹³ , R ¹⁴ ;
R ²⁵ is selected from the group consisting of hydrogen, C ₁ -C ₄ -alkyl, C ₁ -C ₄ -fluoroalkyl, C ₃ -C ₆ -cycloalkyl and C ₃ -C ₆ -cycloalkyl-C ₁ -C ₄ -alkyl Selected from the group;
R 'is selected from the group consisting of hydrogen, C ₁ -C ₄ -alkyl, C ₁ -C ₄ -fluoroalkyl, C ₃ -C ₆ -cycloalkyl and C ₃ -C ₆ -cycloalkyl-C ₁ -C ₄ -alkyl to be. The compound according to claim 1, wherein both Y ¹ and Y ² in Het ¹ are carbon atoms. 3. The compound according to claim 1 or 2, wherein Het ¹ has one heteroatom or heteroatom moiety selected from O, S and NR ^a as a ring member and 0, 1 or 2 additional nitrogen atoms as a ring member Lt; RTI ID = 0.0 &gt; 5-membered &lt; / RTI &gt; heteroaromatic radical. The compound according to claim 3, wherein Het ¹ is 1- (R ^a ) -1 H-pyrazole-3,4-diyl, 1- (R ^a ) -1 H- pyrazole- 1,5-diyl, 1- (R ^a) -1H- imidazole-4,5-diyl, isoxazole-4,5-diyl, isoxazole-3,4-diyl, 1- (R ^a) -1H -1,2,3-triazole-4,5-diyl, 1H-oxazole-4,5-diyl, 1H-imidazole-1,2-diyl, -1, 3, 4-triazole-1, 2-diyl, and k is 0 or 1. 5. Compounds according to any one of claims 1 to 4, wherein k in the formula (I) is 0. 6. Compounds of formula I according to any one of claims 1 to 5, wherein &lt; RTI ID = 0.0 &gt;

/ RTI &gt; to Het1 / 2q: &lt; RTI ID = 0.0 &gt;

&Lt; / RTI &gt;
Wherein R ^a is as defined in claim 1 and R ^b is hydrogen or has one of the meanings given for R. 7. The compound of claim 6, wherein Het1 / 2 is the radical Het1 / 2a. 8. Compounds according to claim 6 or 7, wherein in the radicals Het1 / 2a to Het1 / 2q, R &lt; ^{b &} gt ^; is hydrogen. 9. Compounds of formula I according to any one of claims 1 to 8,

Lt; / RTI &gt;
X ¹ is N or CR ^x1 ;
X ² is N or CR ^x2 ;
X ³ is N or CR ^x3 ;
X ⁴ is N or CR ^x4 ;
Provided that 0, 1 or 2 of X ¹ , X ² , X ³ and X ⁴ is N;
R ^x1 , R ^x2 , R ^x3 , R ^x4 are, independently of each other, hydrogen or have one of the meanings given for R ³ . 10. The method of claim 9, wherein X ¹ is CR ^x1, and X ² is CR ^x2, and X ³ is CR ^x3, and X ⁴ is CR ^x4, where, R ^x1, R ^x2, R ^x3, R ^x4 are each in independently, hydrogen or, have one of the meanings given for R ^3, in particular at least three of R ^x1, R ^x2, R ^x3 and R ^x4 is hydrogen, R ^x1, R ^x2, R ^x3 and R ^x4 &Lt; / RTI &gt; one or less are radicals R &lt; ³ &gt;. 11. Compounds according to claim 9 or 10, wherein each X ¹ , X ² , X ³ and X ⁴ is CH. 12. Compounds of formula IA according to any one of claims 1 to 11, their N-oxides, prodrugs, tautomers and hydrates, and their pharmaceutically acceptable salts.
&Lt;

In the above Formula IA,
Cyc, X ¹ , X ² , X ³ , X ⁴ , Het ² and R ^a are as defined in any one of claims 1 to 11. The compound of formula (I) according to claim 1, the N-oxide, the prodrug, the tautomer and the hydrate thereof, and the pharmaceutically acceptable salts thereof.
&Lt;

In the above formula IA.a,
Cyc, Het &lt; ² &gt; and R &lt; ^a &gt; are as defined in any one of claims 1 to 12. Claim 1 to claim 13 according to any one of wherein, R ^a is, if present, C ₁ -C ₄ - alkyl and C ₁ -C ₄ -, the compound is selected from the group consisting of fluoroalkyl. 15. The compound according to any one of claims 1 to 14, wherein Het ² is phenyl or a heterocyclic group having one heteroatom selected from O, S and N and having one or two selected from O, S, N and NR ^1a 5 or 6 membered monocyclic hetaryl optionally having as ring member an additional heteroatom or heteroatom moiety, wherein said phenyl and said 5 or 6 membered heteroaryl are unsubstituted or are, , 2 or 3 radicals R &lt; ¹ &gt;. 16. Compounds according to any of claims 1 to 15, wherein Het ² is selected from the group consisting of phenyl, oxazolyl, isoxazolyl, furyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyrimidinyl and pyridyl Wherein the radicals mentioned above may be unsubstituted or have 1, 2 or 3 radicals R &lt; ¹ &gt;, wherein R &lt; ^{1 &gt;} is in particular selected from the group consisting of fluorine, chlorine, CN, methyl, difluoromethyl , Trifluoromethyl, methoxy, difluoromethoxy, trifluoromethoxy, and NH ₂ . 17. Compounds according to any one of claims 1 to 16, wherein Het &lt; ² &gt; is 4-pyridyl. The compound according to claim 1, wherein the compound of formula IA. A ', an N-oxide thereof, a prodrug, a tautomer and a hydrate thereof, and a pharmaceutically acceptable salt thereof.
&Lt;

In the above formula IA.a '
Cyc and R &lt; ^a &gt; are as defined in any one of claims 1 to 17. 19. The compound according to any one of claims 1 to 18, wherein Cyc is a C-linked 5-or 6-membered monocyclic hetaryl having 1 or 2 nitrogen atoms as a ring member, benzofuryl, and 1 or 2 Membered 9-membered or 10-membered fused bicyclic hetaryl having a nitrogen atom as a ring member and optionally a further heteroatom selected from O, S and N as a ring member, Wherein the monocyclic hetaryl, benzofuryl and bicyclic hetaryl may be unsubstituted or may have 1, 2, 3 or 4 substituents R &lt; ² &gt;. 18. The compound of claim 17, wherein Cyc has at least one imino-nitrogen located at a position adjacent to the carbon atom bonded to the triple bond as a ring member. 19. The compound of claim 18, wherein Cyc is selected from the group consisting of 2-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 2- pyrazinyl, 3- pyridazinyl, 2- imidazolyl, Thiazolyl, 2-quinolinyl, 3-isoquinolinyl, 2-quinazolinyl, 2-quinoxalinyl, 1,5-naphthyridin-2-yl, 1 , Benzimidazol-2-yl, 1-methylbenzimidazol-2-yl, imidazo [1, Yl, imidazo [2,3-b] pyridin-6-yl, thieno [3,2- b] pyridin- -Thiazol-6-yl and 1,2,4-triazolo [1,5-a] pyridin-2-yl, wherein the radicals mentioned above are selected from the group consisting of fluorine, chlorine, methyl, fluoromethyl , Difluoromethyl, trifluoromethyl, methoxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy, cyclopropyl optionally substituted with one, two or three methyl groups, and fluorinated Lt; RTI ID = 0.0 &gt; 1, &lt; / RTI &gt; The method according to claim 1,
4- (1-methyl-3- (4 - ((1-methyl -1 H-imidazol-ethynyl-5-yl)) phenyl) -1 H-pyrazol-4-yl) pyridine,
2 - ((4- (1-methyl-4- (pyridin-4-yl) -1 H-ethynyl-pyrazol-3-yl) phenyl)) pyridine,
5-methyl-2 - ((4- (1-methyl-4- (pyridin-4-yl) -1 H-ethynyl-pyrazol-3-yl) phenyl)) pyridine,
4- (1-methyl-3- (4 - ((1-propyl -1 H-pyrazol-4-yl) ethynyl) phenyl) -1 H-pyrazol-4-yl) pyridine,
5-fluoro-2 - ((4- (1-methyl-4- (pyridin-4-yl) -1 H-ethynyl-pyrazol-3-yl) phenyl)) pyridine,
3-methyl-2 - ((4- (1-methyl-4- (pyridin-4-yl) -1 H-ethynyl-pyrazol-3-yl) phenyl)) pyridine,
4- (1-methyl-3- (4 - ((1-methyl -1 H-imidazol-ethynyl-2-yl)) phenyl) -1 H-pyrazol-4-yl) pyridine,
4-methyl-2 - ((4- (1-methyl-4- (pyridin-4-yl) -1 H-ethynyl-pyrazol-3-yl) phenyl)) pyridine,
2-methyl-6 - ((4- (1-methyl-4- (pyridin-4-yl) -1 H-ethynyl-pyrazol-3-yl) phenyl)) pyridine,
4- (1-methyl-3- (4 - ((1-methyl -1 H-pyrazol-4-yl) ethynyl) phenyl) -1 H-pyrazol-4-yl) pyridine,
4- (3- (4 - (( 1 H - pyrazol-4-yl) ethynyl) phenyl) -1-methyl -1 H - pyrazol-4-yl) pyridine,
2 - ((4- (1 -methyl-4- (pyridin-4-yl) -lH- pyrazol-3- yl) phenyl) ethynyl) quinoline,
2- [2- [4- [1 -methyl-4- (4-pyridyl) pyrazol-3-yl] phenyl] ethynyl] -1,5-naphthyridine,
Yl] phenyl] ethynyl] imidazo [l, 2-a] pyridine,
LH-pyrrolo [2,3-b] pyridine, l- (2-methylsulfanyl)
Methyl-2- [2- [4- [1 -methyl-4- (4-pyridyl) pyrazol-3-yl] phenyl] ethynyl] quinoline,
2- [2- [4- [1 -methyl-4- (4-pyridyl) pyrazol-3-yl] phenyl] ethynyl] thiazole,
2- [2- [4- [1 -methyl-4- (4-pyridyl) pyrazol-3-yl] phenyl] ethynyl] quinoxaline,
Pyridyl) -2- (4-pyridyl) -6,7-dihydro-5H-pyrrolo [1,2- a] imidazole,
Yl] phenyl] ethynyl] pyridine, 2-methoxy-6- [2- [4- [
3-yl] phenyl] ethynyl] pyridine, &lt; / RTI &gt;
4- [1-methyl-3- [4- (2-phenylethynyl) phenyl] pyrazol-
Pyridyl) ethynyl] phenyl] -2- (4-pyridyl) -6,7-dihydro-5H-pyrrolo [1,2- a ] Imidazole,
5- [1-methyl-3- [4- [2- (6-methyl-2-pyridyl) ethynyl] phenyl] pyrazol-
Yl] phenyl] ethynyl] pyridine, 2-methyl-6- [2- [4- [
Yl] phenyl] ethynyl] pyridine, 2-methyl-6- [2- [4- [
Yl] phenyl] ethynyl] -pyridine, 2-methyl-6- [2- [4- [
4- [1-methyl-3- [4- [2- (6-methyl-2-pyridyl) ethynyl] phenyl] pyrazol-
Yl] phenyl] ethynyl] pyridine, &lt; RTI ID = 0.0 &gt; 2-
Yl] phenyl] ethynyl] -6-methyl-pyridine, &lt; / RTI &gt;
Yl] phenyl] ethynyl] -6-methyl-pyridine, &lt; / RTI &gt;
Yl] phenyl] ethynyl] -6-methyl-pyridine in the presence of a base such as triethylamine, Compounds, and N-oxides, prodrugs, tautomers and hydrates thereof, and pharmaceutically acceptable salts thereof. 23. Compounds according to any one of claims 1 to 22 for use in therapy. 22. A pharmaceutical composition comprising at least one compound as claimed in any one of claims 1 to 22 and at least one excipient. 22. A compound according to any one of claims 1 to 22 for the treatment of a medical disorder selected from a neurological and psychotic disorder capable of being treated by inhibition of phosphodiesterase type 10A. 23. Compounds according to any one of claims 1 to 22 for the treatment of CNS disorders in a mammal. 23. Compounds according to any one of claims 1 to 22 for the treatment of schizophrenia in a mammal. 23. Compounds according to any one of claims 1 to 22 for the treatment of cognitive dysfunctions associated with schizophrenia in a mammal. 23. Compounds according to any one of claims 1 to 22 for the treatment of bipolar disorder in a mammal. 23. Compounds according to any one of claims 1 to 22 for the treatment of depression in a mammal. 23. Compounds according to any one of claims 1 to 22 for the treatment of cognitive dysfunctions associated with Alzheimer's disease in a mammal. 22. The compound according to any one of claims 1 to 22 for the treatment of dietary-induced obesity in a mammal. 23. Compounds according to any one of claims 1 to 22 for the treatment of Huntington's disease in a mammal. 23. Compounds according to any one of claims 1 to 22 for the treatment of anxiety in mammals. Comprising administering an effective amount of at least one compound as claimed in any one of claims 1 to 22 to the treatment of a medical disorder selected from nervous system and psychotic disorders capable of being treated by inhibition of phosphodiesterase type 10A Comprising administering to a subject in need of such treatment a therapeutically effective amount of a medicament selected from the group consisting of a nervous system and a psychotic disorder capable of being treated by inhibition of phosphodiesterase type 10A. 23. Compounds according to any one of claims 1 to 22, comprising isotope labels. The compound of claim 36, wherein the radical R ³ or the radical R ^a is a compound of formula IA, IA.a or IA.a 'as defined in claim 12, 13 or 18, , Compound. 37. The compound according to claim 36 or 37, wherein said isotopic label is selected from positron-emitting isotopic labels, in particular ¹¹ C-labeled and ¹⁸ F-labeled, and gamma-emitting isotopes, in particular ¹²³ I. Use of a compound of claim 38 in positron emission tomography or single photon emission computed tomography. The use of a compound of claim 38 as a PDE10A ligand in brain positron emission tomography or single photon emission computed tomography.